Residence structures and related methods

ABSTRACT

Certain embodiments comprise administering a residence structure to a subject (e.g., a patient) such that the residence structure is retained at a location internal to the subject for a particular amount of time (e.g., at least about 24 hours) before being released. In certain embodiments, the structure has a modular design, combining a material configured for controlled release of therapeutic, diagnostic, and/or enhancement agents with a structural material necessary for gastric residence but configured for controlled and/or tunable degradation/dissolution to determine the time at which retention shape integrity is lost and the structure passes out of the gastric cavity. For example, in certain embodiments, the residence structure comprises a first elastic component, a second component configured to release an active substance, and, optionally, a linker. In some such embodiments, the linker may be configured to degrade.

RELATED APPLICATIONS

This application is a national stage application under 35 U.S.C. § 371of International Patent Application Serial No. PCT/US2015/035423, filedon Jun. 11, 2015, entitled “RESIDENCE STRUCTURES AND RELATED METHODS,”which claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalApplication Ser. No. 62/010,992, filed Jun. 11, 2014, the contents ofwhich are incorporated herein by reference in their entirety for allpurposes

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with Government support under Grant Nos. R37EB000244 and awarded by the National Institutes of Health. TheGovernment has certain rights in the invention.

FIELD OF THE INVENTION

Embodiments described herein generally relate to residence structures,systems, and related methods.

BACKGROUND OF THE INVENTION

Adherence rates of patients to a self-administration protocol fortherapeutics and diagnostics over an extended or indefinite duration isoften poor, with adherence rates for oral therapies for chronicasymptomatic conditions estimated to be less than 50%. The challenge oflow adherence rates is greatest in primary and secondary preventionapplications where a disease to be prevented or treated is oftenasymptomatic and the therapy has no immediate tangible benefit. Manyfactors contribute to low adherence rates including treatment cost,access, side effects, and the inconvenience of dosing regimens.

Current state-of-the-art approaches to improving adherence rates includeeducational interventions, telephone-based counseling, healthinformation technology solutions, interactive pharmacy tools, andchanging models of payment for care, such as no-copayment plans aftermyocardial infarction. All of these approaches have achieved only modestimprovements. Meanwhile, pharmacologic solutions to the adherence rateproblem are generally involve invasive delivery structures and a subsetof pharmacologic agents formulated for extended release. Recent advancesin extended release pharmacologic systems are predominantly limited tosubcutaneous, transdermal, intravaginal, and surgical implants.Conventional solutions include invasive modalities such as surgicalimplants (including, e.g., wireless, programmable structures availablefrom MicroCHIPS, Inc. (Lexington, Mass.)) or modalities limited tospecialized applications such as birth control (including, e.g.,NuvaRing® and Implanon®, both available from Merck & Co., Inc.(Whitehouse Station, N.J.)). Structures like those available fromMicroCHIPS are also limited to delivering therapeutic agents with highpotency because they can be administered in only microgram or smallerquantities.

Oral administration has the potential for the widest patient acceptance;however, no oral delivery system has been demonstrated to enableextended release via the oral route due to a number of fundamentalbarriers. Principally, the transit time for a bolus of food through, forexample, the human gastrointestinal tract is rapid, typically lastingabout 24 to 48 hours and including about 1 to 2 hours in the stomach,about 3 hours in the small intestine, and about 6 to 12 hours in thelarge intestine. One strategy for extended duration therapeuticdelivery, therefore, would be to prolong the transit time of anorally-administered therapeutic (but not food). Gastric residence and/orslowed transit could be attempted and/or tolerated at a number ofsegments of a gastrointestinal tract, as evidenced by bezoars andbariatric structures. Bezoars (i.e., masses found trapped in thegastrointestinal system) can form from a variety of materials that areindigestible (such as food aggregates and hair) and often becomeclinically apparent in adult humans only at sizes in the hundreds ofgrams. A bariatric structure, such as an endoscopically-administeredintra-gastric balloon, can be used to fill a portion of a patient'sstomach to achieve noninvasive gastric reduction for weight loss.Previous attempts at gastric residence for drug delivery includemucoadhesion, gastric swelling, and flotation on gastric fluids.However, none of these approaches have even demonstrated gastricresidence for more than 24 hours, let alone progressed to clinical use.

SUMMARY OF THE INVENTION

Residence structures, systems, and related methods are generallyprovided.

In one aspect, residence structures are provided. In some embodiments,the residence structure comprises a loadable polymeric component, afirst linker coupling the loadable polymeric component to a secondpolymeric component, a second linker comprising at least a portion of orcoupled with the loadable polymeric component and/or the elasticpolymeric component, wherein at least one of the loadable polymericcomponent, the second polymeric component, and the first linker, and thesecond linker comprises an elastic polymeric component, wherein theloadable polymeric component comprises at least about 60 wt % of thetotal structure weight, wherein the residence structure is characterizedby a folding force of at least about 0.2 N, wherein the first linker isdegradable under a first set of physiological conditions, and whereinthe second linker is degradable under a second set of physiologicalconditions different than the first set of conditions and is notsubstantially degradable under the first set of conditions.

In some embodiments, the residence structure comprises a loadablepolymeric component, a second polymeric component coupled to theloadable polymeric component via at least one degradable linkercomprising at least a portion of or coupled with the loadable polymericcomponent and/or the second polymeric component, wherein at least one ofthe loadable polymeric component, the second polymeric component, andthe degradable linker comprises an elastic polymeric component, whereinthe loadable polymeric component comprises at least about 60 wt % of thetotal structure weight, wherein the residence structure has a foldingforce of at least about 0.2 N, and wherein the residence structure hasan uncompressed cross-sectional dimension of at least about 2 cm.

In some embodiments, the residence structure comprises a loadablepolymeric component and a second polymeric component coupled with theloadable polymeric component, at least one degradable linker comprisingat least a portion of or coupled with the loadable polymeric componentand/or the second polymeric component, wherein the residence structureis configured such that it is retained at a location internally of asubject for at least about 24 hours.

In some embodiments, the residence structure comprises a loadablepolymeric component and a second polymeric component coupled with theloadable polymeric component, at least one degradable linker comprisingat least a portion of or coupled with the loadable polymeric componentand/or the second polymeric component, wherein the loadable polymericcomponent comprises an active substance, the residence structure isconfigured such that the active substance is released from the loadablepolymeric material at a particular initial average rate as determinedover the first 24 hours of release, and wherein the active substance isreleased at an average rate of at least about 1% of the initial averagerate over a 24 hour period after the first 24 hours of release.

In another aspect, systems are provided. In some embodiments, the systemcomprises a containing structure, a residence structure contained withinthe containing structure, wherein the residence structure is constructedand arranged to have a first configuration after release from thecontaining structure, wherein the residence structure is constructed andarranged to have a second configuration when contained within thecontaining structure, wherein the first configuration has anuncompressed cross-sectional dimension of at least about 2 cm, andwherein the second configuration has a convex hull at least about 10%less than a convex hull of the first configuration and/or wherein thesecond configuration has a largest cross-sectional dimension at leastabout 10% less than a largest cross-sectional dimension of the firstconfiguration, and wherein a first portion of the device is degradableunder a first set of physiological conditions, while a second portion ofthe device is not substantially degradable under the first set ofphysiological conditions.

In another aspect, methods for delivering a residence structure areprovided. In some embodiments, the method comprises administering, to asubject, a containing structure comprising a residence structure, suchthat the containing structure releases the residence structure at alocation within the subject, wherein the residence structure has asecond configuration within the containing structure, wherein, after theresidence structure is released from the containing structure, theresidence structure obtains a first configuration such that theresidence structure is retained at or in proximity to the locationwithin the subject for at least about 24 hours.

In some embodiments, the method comprises administering, to a subject, acontaining structure comprising a residence structure, such that thecontaining structure releases the residence structure at a locationwithin the subject, wherein the residence structure has a secondconfiguration within the containing structure, the residence devicecomprises a loadable polymeric component that comprises an activesubstance, the residence structure is configured such that the activesubstance is released from the residence structure at an initial averagerate over the first 24 hours of release, and the active substance isreleased at an average rate of at least about 1% of the initial averagerate over a 24 hour period after the first 24 hours of release.

In another aspect, a containing structure is constructed and arranged tobe administered, to a subject, the containing structure comprising aresidence structure, such that the containing structure releases theresidence structure at a location within the subject, wherein theresidence structure has a second configuration within the containingstructure, wherein, after the residence structure is released from thecontaining structure, the residence structure obtains a firstconfiguration such that the residence structure is retained at or inproximity to the location within the subject for at least about 24hours.

In some embodiments, a containing structure is constructed and arrangedto be administered, to a subject, the containing structure comprising aresidence structure, such that the containing structure releases theresidence structure at a location within the subject, wherein theresidence structure has a second configuration within the containingstructure, the residence device comprises a loadable polymeric componentthat comprises an active substance, the residence structure isconfigured such that the active substance is released from the residencestructure at an initial average rate over the first 24 hours of release,and the active substance is released at an average rate of at leastabout 1% of the initial average rate over a 24 hour period after thefirst 24 hours of release.

In some embodiments, the system comprises at least one residencestructure configured to administer the at least one of a therapeuticagent, a diagnostic agent, and an enhancement agent during a residencetime period longer than at least twenty-four hours, the at least oneresidence structure having a first shape configured to maintain an invivo position relative to an internal orifice during the residence timeperiod, the at least one residence structure comprising at least oneenteric elastomer linker positioned such that a level of dissociation ofthe at least one enteric elastomer linker ends the residence time periodand allows the at least one residence structure to pass through theinternal orifice.

In some embodiments, the system comprises at least one residencestructure configured to at least one of transport and maintain the atleast one structure during a residence time period longer than at leasttwenty-four hours, the at least one residence structure having a firstshape configured to maintain an in vivo position relative to an internalorifice during the residence time period, the at least one residencestructure comprising at least one enteric elastomer linker positionedsuch that a level of disassociation of the at least one entericelastomer linker ends the residence time period and allows the at leastone residence structure to pass through the internal orifice.

In some embodiments, the at least one enteric elastomer linker isconfigured to disassociate at least in part over the retention timeperiod.

In some embodiments, the at least one retention structure is loaded withthe at least one of a therapeutic agent, a diagnostic agent, and anenhancement agent before administering the at least one retentionstructure to the subject.

In some embodiments, after administering the at least one retentionstructure to the subject, the at least one retention structure is loadedwith the at least one of a therapeutic agent, a diagnostic agent, and anenhancement agent in vivo.

In some embodiments, the retention time period is more than at least oneof 24 hours, one week, two weeks, four weeks, and one year.

In some embodiments, the system further comprises at least onecontaining structure, each configured to maintain a retention structurein a second shape configured for packing into a containing structure.

In some embodiments, the at least one containing structure is configuredto be at least one of ingested, self-administered, and orallyadministered.

In some embodiments, the at least one containing structure comprises atleast one of a 000 capsule, 00 capsule, 0 capsule, 1 capsule, 2 capsule,3 capsule, 4 capsule, and 5 capsule.

In some embodiments, the second shape is configured such that theretention structure occupies a volume more than 60% of a cavity definedby the containing structure.

In some embodiments, the retention structure is configured to adopt thefirst shape upon release from the containing structure.

In some embodiments, prior to release from the containing structure theretention structure is stored in the second shape in the containingstructure for more than at least one of 72 hours, one week, two weeks,four weeks, one year, and five years.

In some embodiments, the at least one retention structure furthercomprises a deformable material, the first shape comprises an ellipticaloutline in a first plane with a major axis and a minor axis, the secondshape comprises a helix such that an axis of the helix is along theminor axis, and at least one enteric elastomer linker is disposed alongthe minor axis.

In some embodiments, at least one enteric elastomer linker is disposedalong the major axis.

In some embodiments, the at least one retention structure furthercomprises a core and a plurality of radial projections at least one ofattached to and incorporated with the core, the first shape comprisesthe plurality of projections projecting from the core in a plurality ofdirections, and the second shape comprises the plurality of projectionsprojecting from the core in a substantially parallel direction to eachother.

In some embodiments, the at least one enteric elastomer linker comprisesa first enteric elastomer linker disposed along a first radialprojection in the plurality of radial projections.

In some embodiments, the at least one enteric elastomer linker comprisesa first enteric elastomer linker connecting a first radial projection inthe plurality of radial projections to the core.

In some embodiments, the core comprises the at least one entericelastomer linker.

In some embodiments, a first radial projection in the plurality ofradial projections has a length corresponding to a maximum dimension ofthe containing structure.

In some embodiments, the plurality of radial projections are arrangedsuch that the plurality of radial projections define N internal sectorangles of approximately 360°/N, where N is the total number of radialprojections.

In some embodiments, the at least one retention structure furthercomprises a deformable material, the first shape comprises a polygonoutline in a first plane, the second shape comprises each side of thepolygon outline folded, and at least one enteric elastomer linker ispositioned at each vertex of the polygon outline.

In some embodiments, a first side of the polygon outline has a lengthcorresponding to the length of the containing structure.

In some embodiments, each of the sides defines an internal sector angleof approximately 360°/N, where N is the total number of sides.

In some embodiments, the at least one retention structure furthercomprises a deformable material, the first shape comprises a circularring, the second shape comprises the circular ring folded intoquadrants, and at least one enteric elastomer linker is positioned ateach vertex of each arc of the quadrants.

In some embodiments, the at least one retention structure furthercomprises a core and a plurality of small rounded loops at least one ofattached to and incorporated with the core, the small rounded loopscomprising a shape memory alloy, the core comprising at least oneenteric elastomer linker, the first shape comprises the plurality ofsmall rounded loops extending from the core, and the second shapecomprises the plurality of small rounded loops folded against the core.

In some embodiments, the first shape is configured to prolong a transittime through at least part of the subject's gastrointestinal tract by atleast the retention time period.

In some embodiments, the first shape is configured to maintain the atleast one retention structure in a gastric cavity of the subject duringat least the retention period.

In some embodiments, the internal orifice is a pyloric orifice.

In some embodiments, the at least one retention structure is loaded witha mass of the at least one of a therapeutic agent, a diagnostic agent,and an enhancement agent formulated for release.

In some embodiments, exposure to at least one of an alkali solution, theat least one enteric elastomer linker accelerates disassociation of atleast one enteric elastomer linker.

In some embodiments, exposure to at least one of an alkali solution, theat least one enteric elastomer linker accelerates dissociation of the atleast one enteric elastomer linker to the level of dissociation endingthe retention time period and allowing the at least one retentionstructure to pass through the internal orifice.

In some embodiments, the at least one retention structure furthercomprises at least one material configured for drug loading via at leastone of solvent loading, melt loading, physical blending, supercriticalcarbon dioxide, and conjugation reactions.

In some embodiments, the at least one material configured for drugloading is further configured to administer at least one loaded drug viaat least one of diffusion and slow matrix degradation, dissolution,degradation, swelling, diffusion of the at least one loaded drug, anionic gradient, hydrolysis, and cleavage of the conjugating bonds.

In some embodiments, the at least one enteric elastomer linker isdifferent from the delivery material and configured to at leastpartially resist drug loading.

In some embodiments, the at least one enteric elastomeric linkercomprises an enteric polymer comprising a polymer of anacryloylaminoalkylene acid monomer, or salts thereof.

In some embodiments, the acryloylaminoalkylene acid monomer is selectedfrom the group consisting of acryloyl-5-aminopentanoic acid,acryloyl-6-aminocaproic acid, acryloyl-7-aminoheptanoic acid,acryloyl-8-aminooctanoic acid, acryloyl-9-aminonoanoic acid,acryloyl-10-aminodecanoic acid, acryloyl-11-aminoundecanoic acid,acryloyl-12-aminododecanoic acid, methacryloyl-5-aminopentanoic acid,methacryloyl-6-aminocaproic acid, methacryloyl-7-aminoheptanoic acid,methacryloyl-8-aminooctanoic acid, methacryloyl-9-aminonoanoic acid,methacryloyl-10-aminodecanoic acid, methacryloyl-11-aminoundecanoicacid, methacryloyl-12-aminododecanoic acid, salts thereof, andcombinations thereof.

In some embodiments, the at least one enteric elastomeric linkercomprises an enteric polymer blend of at least two enteric polymers,comprising a first enteric polymer of claim 37 and a second entericpolymer comprising poly(methacrylic acid-co-alkyl acrylate), or saltsthereof.

In some embodiments, the first enteric polymer is a homopolymer ofacryloyl-6-aminocaproic acid or salts thereof.

In some embodiments, the first enteric polymer is a copolymer ofacryloyl-6-aminocaproic acid or salts thereof.

In some embodiments, the second enteric polymer is poly(methacrylicacid-co-ethyl acrylate) or salts thereof.

In some embodiments, the poly(methacrylic acid-co-ethyl acrylate) has amolar ratio of methacrylic acid monomer units to ethylacrylate monomerunits of about 1:1.

In some embodiments, the first enteric polymer is a homopolymer ofacryloyl-6-aminocaproic acid.

In some embodiments, the at least one enteric elastomeric linkercomprises an enteric polymer composition comprising a first entericpolymer of claim 37, or salts thereof, and optionally a second entericpoly(methacrylic acid-co-ethyl acrylate), or salts thereof, wherein theweight ratio of the first enteric polymer to the second enteric polymerranges from about 1:0 to about 1:3.

In some embodiments, the weight ratio of the first enteric polymer tothe second enteric polymer ranges from 1:0 to about 1:2.

In some embodiments, the enteric polymer blend is in the form of apolymer gel.

In some embodiments, said polymer gel has a water content of less thanabout 50% by weight.

In some embodiments, the polymer gel as a water content of less thanabout 40% by weight.

In some embodiments, the enteric polymer blend exhibits reversibleelongation when stretched from 50% to 1500% of its initial length.

In some embodiments, said blend dissolves in an aqueous solution at a pHgreater than about 6.0, and is insoluble when immersed in an aqueoussolution at a pH less than about 3.0, measured at room temperature overa time period of 4-40 days.

In some embodiments, the enteric polymer blend has a Young's modulus offrom 0.1 MPa to 100 MPa.

In some embodiments, the enteric polymer blend exhibits reversibleelongation when stretched from 50% to 1500% of its initial length.

One aspect of the present invention contemplates a gastric retentiondevice comprising a central elastic polymeric component coupled tobetween three and eight loadable polymeric components, each loadablepolymeric component projecting radially from the central elasticpolymeric component to form a star-like cross-sectional shape, whereineach of the loadable polymeric components is coupled to the centralelastic polymeric component. A first degradable linker is present ineach loadable polymeric component near or at the interface with theelastic polymeric component. by a first degradable linker. In certainembodiments, the loadable polymeric components further comprise a seconddegradable linker that may be the same as or different from the firstdegradable linker. In certain embodiments, the loadable polymericcomponents comprise polycaprolactone, polylactic acid, polylacticco-glycolic acid and/or mixtures thereof and may further compriseexcipients, and the degradable linker is a water soluble and/ordegradable polymer and blends thereof, including but not limited to,Polyvinylpyrrolidone, polyvinyl alcohol, Kollidon VA 64, polyorthoester,Polyhydroxybutyrate, Eudragits and mixtures thereof. The device mayfurther comprise at least one of a one of a therapeutic agent, adiagnostic agent, and an enhancement agent, wherein the therapeuticagent is selected from a hydrophilic drug, a hydrophobic drug,artemether, ivermectin, risperidone, doxycycline, an anti-malarialagent, an anti-helminth agent, an antipsychotic agent, and anantibiotic.

The devices of these embodiments can be contained within a solublecontainer such as one composed of gelatin and which may optionallycomprise excipients. In certain embodiments, the device has a minimumuncompressed cross-sectional dimension of about 3-5.5 cm, of about 3 cm,of about 4 cm, of about 5 cm, or of about 5.5 cm. Intermediate minimumuncompressed cross-sectional dimensions are also contemplated. Incertain embodiments, the loadable polymeric components have a lengthapproximately equal to the length of a soluble container such that theunencapsulated form has a diameter equal to nearly twice the length ofthe soluble container. In certain embodiments, the loadable polymericcomponents have a length of between about 1.3 and about 2.7 cm. It iscontemplated that the gastric retention devices of the above embodimentsmay be retained within the gastric cavity for between 24 hours and about1 month, or between about 24 hours and 10 days.

Another aspect of the invention is a gastric retention device comprisinga central elastic polymeric component comprising a polyurethane, whereinthe elastic polymeric component is coupled to six loadable polymericcomponents, each loadable polymeric component projecting radially fromthe central elastic polymeric component to form a star-likecross-sectional shape, wherein each of the loadable polymeric componentsis coupled to the central elastic polymeric component by atime-dependent degradable linker, and wherein the loadable polymericcomponents further comprise an embedded linker comprising an entericpolymer. In certain embodiments, the loadable polymeric componentscomprise polycaprolactone and may optionally comprise excipients, andthe degradable linker is a water soluble and/or degradable polymer andblends thereof, including but not limited to, Polyvinylpyrrolidone,polyvinyl alcohol, Kollidon VA 64, polyorthoester, Polyhydroxybutyrate,Eudragits and mixtures thereof. In certain embodiments, the device iscontained within a soluble container that may optionally compriseexcipients. The device may further comprise at least one of a one of atherapeutic agent, a diagnostic agent, and an enhancement agent, whereinthe therapeutic agent is selected from a hydrophilic drug, a hydrophobicdrug, artemether, ivermectin, risperidone, doxycycline, an anti-malarialagent, an anti-helminth agent, an antipsychotic agent, and anantibiotic.

In certain embodiments, the device has a minimum uncompressedcross-sectional dimension of about 3-5.5 cm, of about 3 cm, of about 4cm, of about 5 cm, or of about 5.5 cm. Intermediate minimum uncompressedcross-sectional dimensions are also contemplated. In certainembodiments, the loadable polymeric components have a lengthapproximately equal to the length of a soluble container such that theunencapsulated form has a diameter equal to nearly twice the length ofthe soluble container. In certain embodiments, the loadable polymericcomponents have a length of between about 1.3 and about 2.7 cm.

It is contemplated that the gastric retention devices of these aboveembodiments may be retained within the gastric cavity for between 24hours and about 1 month, or between about 24 hours and 10 days. Incertain embodiments the linker comprising an enteric polymer degrades inresponse to a pH greater than about 5, such that the loadable polymericcomponents break apart.

In some embodiments, the method comprises administering to a subject atleast one residence structure configured to administer the at least oneof a therapeutic agent, a diagnostic agent, and an enhancement agentduring a residence time period longer than at least twenty-four hours,the at least one residence structure having a first shape configured tomaintain an in vivo position relative to an internal orifice during theresidence time period, the at least one residence structure comprisingat least one enteric elastomer linker positioned such that a level ofdisassociation of the at least one enteric elastomer linker ends theresidence time period and allows the at least one residence structure topass through the internal orifice.

In some embodiments, the method comprises administering to a subject atleast one residence structure configured to at least one of transportand maintain the at least one structure during a residence time periodlonger than at least twenty-four hours, the at least one residencestructure having a first shape configured to maintain an in vivoposition relative to an internal orifice during the residence timeperiod, the at least one residence structure comprising at least oneenteric elastomer linker positioned such that a level of disassociationof the at least one enteric elastomer linker ends the residence timeperiod and allows the at least one residence structure to pass throughthe internal orifice.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIGS. 1A-1C are schematic diagrams of a residence structure, accordingto one set of embodiments;

FIG. 1D is a schematic diagram illustrating the convex hull volume of astructure, according to one set of embodiments;

FIGS. 1E-1F are schematic diagrams of exemplary configurations of aresidence structure, according to one set of embodiments;

FIGS. 1G-1H are schematic diagrams of other exemplary configurations ofa residence structure, according to one set of embodiments;

FIG. 2 is a reproduction of a photograph of an exemplary residencestructure and a strategy for folding the structure, according to one setof embodiments;

FIGS. 3A-3E are reproductions of photographs of an exemplary residencesystem and structure, showing (A) an exemplary structure and anencapsulating structure; (B) the exemplary structure folded within theencapsulating structure; (C) another view of an exemplary structure; (D)the exemplary structure twisted; and (E) the exemplary structure of (D)twisted within the encapsulating structure, according to one set ofembodiments;

FIGS. 4A-4C are illustrations of (A) an exemplary residence structurecomprising projections, and a capsule for containment according to oneset of embodiments, (B) illustrations of various exemplary residencestructures comprising projections, and (C) reproductions of photographsof exemplary residence structures;

FIGS. 5A-5B are illustrations and photographs of an exemplary polygonalresidence structure, according to one set of embodiments;

FIG. 6 is a series of X-ray images obtained in a large animal model witha residence structure, according to one set of embodiments;

FIG. 7 is a series of X-ray images obtained in a large animal model witha residence structure, according to one set of embodiments;

FIG. 8A is an illustration of an enteric elastomer for use in aresidence structure, according to one set of embodiments;

FIG. 8B is an illustration of the preparation of an enteric elastomerfor use in a residence structure, according to one set of embodiments;

FIG. 8C is a series of reproductions of photographs obtained duringmechanical testing of an enteric elastomer, according to one set ofembodiments;

FIG. 9A is illustrates materials tested and results obtained for themechanical characterization of several exemplary enteric elastomers,according to one set of embodiments;

FIG. 9B is a plot showing the dissolution characterization of an entericelastomer, according to one set of embodiments;

FIG. 9C is a plot of cell viability (i.e. cytotoxicity) of an entericelastomer, according to one set of embodiments;

FIG. 10 are illustrations showing the construction and in vivoevaluation of the ring-shaped residence structure, according to one setof embodiments;

FIG. 11A is a plot of stress (MPa) vs. strain (mm/mm) for an elasticpolymeric component of an exemplary structure, according to one set ofembodiments;

FIG. 11B is a plot of pressure (MPa) vs. strain (mm/mm) for an elasticpolymeric component of an exemplary structure, according to one set ofembodiments;

FIG. 11C is a plot of creep strain (mm/mm) vs. time (sec) for variouselastic polymeric components of an exemplary structure, according to oneset of embodiments;

FIG. 12 are isometric, top, bottom, and side views of a finite elementmodeling simulation of a residence structure undergoing deformation,according to one set of embodiments;

FIG. 13A is a schematic illustration of a residence structure testingapparatus, according to one set of embodiments;

FIG. 13B is a plot of force vs. displacement for a residence structureusing the testing apparatus of FIG. 13A, according to one set ofembodiments;

FIG. 14 is a plot of the stability of Doxycycline in SGF (pH=1, 37° C.)over two weeks as analyzed by High Performance Liquid Chromatography(HPLC), according to one set of embodiments;

FIG. 15 is a plot of the stability of Artemether in isopropanol 70%,acetonitrile 20%, water 10% (IAW) (pH=1, 37° C.) over two weeks asanalyzed by HPLC, according to one set of embodiments;

FIGS. 16A-B are plots of the stability of Ivermectin (A) in solution or(B) in polycaprolactone (PCL) structures in acidic conditions (pH=1, 37°C.), according to one set of embodiments;

FIG. 17A is a plot that shows the in vitro release of doxycycline loadedPCL stars in simulated gastric fluid (SGF) (pH=1, 37° C.), according toone set of embodiments;

FIG. 17B is a plot that shows in vitro release of Ivermectin (IVM)loaded star-shaped structures with different formulations in SGF andKolliphor® RH40, a non-ionic oil-in-water solubilizing agent (RH40),(pH=1, 37° C.), according to one set of embodiments;

FIG. 17C is a plot that shows the in vitro release of IVM loadedstar-shaped structures with different formulations in SGF+RH40 (pH=1,37° C.), according to one set of embodiments;

FIG. 18 is a plot that shows the mechanical characterization accordingto ASTM standard D790 of various PCL based materials, according to oneset of embodiments;

FIG. 19 is a plot that shows the probability of gastric retention atspecified time points of a configurations of a gastric residencestructure, according to one set of embodiments;

FIG. 20 is a plot that shows the probability of gastric retention atspecified time points of a configurations of a gastric residencestructure, according to one set of embodiments;

FIG. 21 is a plot that shows the probability of gastric retention atspecified time points of a configurations of a gastric residencestructure, according to one set of embodiments;

FIG. 22 is a reproduction of a photograph that shows endoscopicevaluation at day 35 of retention of a stellate delivery system,according to one set of embodiments;

FIG. 23 is a plot that shows the cumulative release of risperidone overtime for an exemplary residence structure, according to one set ofembodiments;

FIG. 24 are plots that show the release of doxycycline over time for anexemplary residence structure versus a doxycycline pill, according toone set of embodiments;

FIGS. 25A-C are plots that show the release of ivermectin over time for(A) an ivermectin pill, (B) a lower dose formulation, and (C) a higherdose formulation, according to one set of embodiments; and

FIG. 26 is a plot that shows the release of doxycycline over time for anexemplary residence structure, according to one set of embodiments.

DETAILED DESCRIPTION

Residence structures, systems, and related methods are generallydisclosed. Certain embodiments comprise administering (e.g., orally) aresidence structure to a subject (e.g., a patient) such that theresidence structure is retained at a location internal to the subjectfor a particular amount of time (e.g., at least about 24 hours) beforebeing released or partially released. The residence structure may be, insome cases, a gastric residence structure. In some embodiments, thestructures and systems described herein comprise one or more materialsconfigured for one or more of (and in any combination) active substances(e.g., a therapeutic agent) loading (in some cases at relatively highlevels), active substance and/or structure stability in acidicenvironments, mechanical flexibility and strength when contained in aninternal cavity (e.g., gastric cavity), easy passage through the GItract until delivery to a desired internal cavity (e.g., gastriccavity), and/or rapid dissolution/degradation in a physiologicalenvironment (e.g., intestinal environment) and/or in response to achemical stimulant (e.g., ingestion of a solution to induce accelerateddissolution/degradation). In certain embodiments, the structure has amodular design, combining a material configured for controlled releaseof therapeutic, diagnostic, and/or enhancement agents with a structuralmaterial facilitating gastric residence and configured for controlledand/or tunable degradation/dissolution to control the time at which aretention shape integrity is lost to permit the structure to pass out ofthe gastric cavity. For example, in certain embodiments, the residencestructure comprises a first elastic component, a second polymericcomponent configured to release an active substance (e.g., a therapeuticagent), and, optionally, at least one linker. In some such embodiments,the linker may be configured to degrade such that the residencestructure breaks apart and is released from the location internally ofthe subject after a predetermined amount of time and/or when exposed toa select set of conditions.

In some embodiments, the residence structure has a particularconfiguration including a particular size and/or shape (e.g., amulti-armed star) in a relaxed state. In certain embodiments, theresidence structure may be folded from the relaxed state into a second,compressed configuration. For example, in some cases, thefolded/compressed residence structure may be inserted within a capsuleor other containment structure in the second configuration such that theresidence structure can be delivered orally. The capsule or othercontainment structure can be, in some cases, configured to dissolve suchthat the residence structure is released at a particular locationinternal to the subject (e.g., in the stomach) whereby upon release, itcan reversibly revert to the first configuration (e.g. by. recoil). Insome embodiments, the structure is configured to adopt a shape and/orsize in vivo that slows or prevents further transit in a body (e.g.,gastric) cavity (e.g., passage from the body of the stomach through thepylorus.) In some embodiments, the structure adopts a shape and/or sizeconfigured for retention (e.g., gastric residence) upon release from asoluble capsule/container and/or soluble retaining structure/element. Insome embodiments, the structure is configured for adopting a shapeand/or size configured for gastric residence after being stored in itsencapsulated shape and/or size for durations greater than 24 hours,including up to about one year. In some embodiments, the mechanicalproperties of the structure are optimized for safe transient retentionof all or a portion of the structure in an internal cavity such as thegastric cavity for durations greater than 24 hours, including up toabout one year.

Certain of the structures, systems, and methods described herein can beuseful, for example, in achieving gastric residence and/or slowedtransit via oral administration for extended in vivo residence andadministration of therapeutic, diagnostic, and/or enhancement agents.Certain embodiments of structures and systems described herein may offercertain advantages as compared to traditional compositions andstructures and systems configured for internal retention and/or drugrelease, for example, in their ability to adopt a shape and/or sizesmall enough to be ingested by a subject; adopt a shape and/or sizeinternally that slows or prevents further transit in a body cavity (e.g.the gastric cavity) (e.g., passage from the body of the stomach throughthe pylorus); be loaded at high levels (e.g., high mass fraction) withtherapeutic, diagnostic, and/or enhancement agents; facilitatecontrolled release of such therapeutic, diagnostic, and/or enhancementagents with low to no potential for burst release; maintainactivity/stability of such therapeutic, diagnostic, and/or enhancementagents in a hostile environment such as the gastric environment for anextended duration; maintain safety with low to no potential for gastricor intestinal obstruction and/or perforation; and/ordegrade/dissolve/disassociate into one or more forms configured forpassing through a gastrointestinal tract. In certain embodiments, thestructures and systems described herein can be configured with durableresidence times greater than at least twenty-four hours and lasting upto about one year, or more. In some embodiments, the systems,structures, and methods described herein are compatible with subjects,including, but not limited to, humans and non-human animals. In furtherembodiments, the systems and structures can be configured to deliver awide variety of therapeutic, diagnostic, and/or enhancement agents, thuspotentially increasing and even maximizing patient treatment therapyadherence rates.

The structures and systems described herein may bemodular/multi-component (i.e. formed of multiple interconnectedsubcomponents.) In some embodiments, the structure comprises one or morepolymeric components configured for containing and/or releasing atherapeutic agent, and/or configured for undergoing mechanicaldeformation such that the component(s) does not permanently deformand/or break, and/or configured to recoil after a particular amount oftime such that the structure can be selectively retained at a locationinternally of a subject. In certain embodiments, the structure comprisestwo or more polymeric components. For example, in some cases, thestructure comprises a first polymeric component and a second polymericcomponent different than, and in direct contact with, the firstpolymeric component. As illustrated in FIG. 1A, in some embodiments,structure 100 comprises first polymeric component 110 coupled withsecond polymeric component 120. In some such embodiments, the firstpolymeric component may be coupled with the second polymeric componentvia an adhesive, by chemical interactions (e.g., chemical bonds), and/orby interpenetrating and/or entangled polymer chains, and/or with otherphysical, chemical, and/or associative interactions. In someembodiments, the first polymeric component is an elastic polymericcomponent and the second polymeric component is a loadable polymericcomponent. Elastic polymeric components and loadable polymericcomponents are described in more detail, below.

In general, embodiments of the invention may be practiced with anycombinations of first, second, third, etc. polymer components, but thatfor clarity and conciseness, much of the following description is in thecontext of select embodiments that include an elastic polymericcomponent and a loadable polymeric component.

In some embodiments, one or more linkers are associated with the one ormore polymeric components. For example, in some embodiments, the linkeris embedded within and may separate or link two or more portions of anelastic polymeric component. In certain embodiments, the linker isembedded within and may separate or link two or more portions of aloadable polymeric component. In some cases, the linker is positionedbetween two or more different polymeric components (e.g., to couple tothe two or more different polymeric components). For example, in someembodiments, two elastic polymeric components are coupled by a linker.In certain embodiments, two loadable polymeric components are coupled bya linker. In some cases, an elastic polymeric component is coupled to aloadable polymeric component by a linker. In some embodiments, thestructure may comprise a combination of arrangements of polymericcomponents and linkers.

In certain embodiments, a first polymeric component and a secondpolymeric component are coupled by a linker. For example, as illustratedin FIG. 1B, structure 100 comprises first polymeric component 110coupled with a second polymeric component 120 via linker 130. Linkersand suitable linker materials are described in more detail, below.

In some embodiments, the linker is embedded within and may separate orlink two or more portions of a first polymeric component or a secondpolymeric component. For example, in certain embodiments, the linkerdoes not couple the first polymeric component and the second polymericcomponent, but is embedded within the first polymeric component or thesecond polymeric component and may separate or link two or more portionsof such component, such that when the linker degrades the componentbreaks apart (e.g., such that the structure or a part of the structureis removed).

In some embodiments, the structure is designed such that the mechanismfor delivery is different from the mechanism for degradation. Forexample, linkers (e.g., enteric linkers described below) may be attachedto, fused to, bonded with, embedded within, or otherwise associated witha loadable material (e.g., a loadable polymeric component) whichcomprises the bulk of the structure. Materials may be selected so thatwhen the loadable material/linker composite is exposed to therapeutic,diagnostic, and/or enhancement agents for loading, loading may beselective within the loadable material, with release of therapeutic,diagnostic, and/or enhancement agents from the loadable materialoccurring via diffusion or slow matrix degradation. In some embodiments,the loadable material has particular mechanical properties such that theloadable material resists brittle breakage but is sufficiently stiffsuch that it may withstand internal physiological mechanical, chemical,and/or biological challenges to facilitate the ability to maintainresidence of the structure or at least the loaded material components ofthe structure for a desired time interval. In some embodiments, loadingof such therapeutic, diagnostic, and/or enhancement agents may beminimized within the separate linker material, and the separate linkermaterial may be configured for control/tuning of degradation/dissolutionof the retention/delivery structure and/or certain of the loadablematerial portions of the retention/delivery structure. By separating themechanism of delivery (e.g., slow release from relatively stableloadable material portions) from the mechanism of controllabledegradation (e.g., more rapid degradation of the linker(s), theretention/delivery structure may be advantageously configured to preventburst release of therapeutic, diagnostic, and/or enhancement agents upondegradation/dissolution.

In some embodiments, the structure comprises multiple polymericcomponents and/or multiple linkers. In certain embodiments, thestructure comprises one or more, two or more, three or more, four ormore, or five or more polymeric components of a first material. In someembodiments, the structure comprises one or more, two or more, three ormore, four or more, or five or more polymeric components of a secondmaterial. More complex structures and more types of polymeric materialsare possible. In certain embodiments, the structure comprises one ormore, two or more, three or more, four or more, or five or more, etc.linkers. In an illustrative embodiment, as illustrated in FIG. 1C,structure 100 comprises a polymeric component 110 of a first typecoupled with two polymeric components 120 of a second type via twolinkers 130. Those skilled in the art would be capable of selectingadditional various arrangements of polymeric components and linkersbased upon the teachings of the specification. Additional exemplaryarrangements are described in more detail below.

In some embodiments, the retention structure comprises an elasticpolymeric component. In certain embodiments, the use of an elasticpolymeric component may impart favorable mechanical properties to thestructure. For example, in some cases, the structure may be configuredfor undergoing relatively high compressive forces (e.g., compressiveforces present within the stomach and/or intestine of a subject) suchthat the structure does not break and/or is retained at a locationinternally of the subject (e.g., at or above an orifice such as thepylorus). In certain embodiments, the structure may be configured forbeing folded (e.g., without breaking). For example, the elasticpolymeric component may be configured for undergoing relatively highlevels of bending stresses without breaking and/or without beingpermanently significantly deformed. In some embodiments, the elasticpolymeric component and/or the structure containing it may be configuredfor substantial recoil. That is to say, after mechanically deforming theelastic polymeric component and/or the structure comprising the elasticpolymeric component, the structure may return substantially to itsoriginal configuration prior to the mechanical deformation being applied(e.g., the elastic polymeric component may be characterized bysubstantially minimal creep deformation).

Appropriate screening tests may be used to determine suitable materialsfor use as the elastic polymeric component. For example, the elasticpolymeric component may be tested for the capability of undergoing atleast about 45 degrees, at least about 60 degrees, at least about 90degrees, at least about 120 degrees, at least about 150 degrees, orabout 180 degrees of mechanical bending deformation without breaking. Incertain embodiments, the elastic polymeric component may be configuredfor undergoing up to and including about 180 degrees, up to andincluding about 150 degrees, up to and including about 120 degrees, upto and including about 90 degrees, or up to and including about 60degrees of mechanical bending deformation without breaking. Any and allclosed ranges that have endpoints within any of the above-referencedranges are also possible (e.g., between about 45 degrees and about 180degrees, between about 60 degrees and about 180 degrees, between about60 degrees and about 120 degrees, between about 90 degrees and about 180degrees). Other ranges are also possible.

In some cases, the elastic polymeric component may be configured forremaining in a deformed configuration (e.g., at least about 45 degreesof mechanical bending deformation) for a relatively prolonged period oftime—for example, in some embodiments, the elastic polymer component hasa shelf-life in such a deformed configuration of at least about 24hours, at least about 1 week, at least about 1 month, at least about 1year, or at least about 2 years—and still be configured for returning(i.e. recoiling) substantially to its pre-deformation configuration. Incertain embodiments, the elastic polymer component has a shelf life in adeformed configuration of up to and including about 3 years, up to andincluding about 2 years, up to and including about 1 year, up to andincluding about 1 month, or up to and including about 1 week and beconfigured for returning (i.e. recoiling) substantially to itspre-deformation configuration. Any and all closed ranges that haveendpoints within any of the above-referenced ranged are also possible(e.g., between about 24 hours and about 3 years, between about 1 weekand 1 year, between about 1 year and 3 years). Other ranges are alsopossible.

In some embodiments, the elastic polymeric component is relativelyflexible. In certain embodiments, the elastic polymeric component may beselected such that it is configured for undergoing large angledeformation for relatively long periods of time without undergoingsignificant non-elastic deformation. In some such embodiments, theelastic polymeric component may have a strength of recoil sufficient tosubstantially return the elastic polymeric component to its pre-deformedshape within less than about 30 minutes, within less than about 10minutes, within less than about 5 minutes, or within less than about 1minute after release of the mechanical deformation. Those skilled in theart would understand that returning to its pre-deformed shape shall beunderstood to not require absolute conformance to a mathematicaldefinition of shape, but, rather, shall be understood to indicateconformance to the mathematical definition of shape to the extentpossible for the subject matter so characterized as would be understoodby one skilled in the art most closely related to such subject matter.

In some embodiments, the elastic polymeric component has a particularelastic modulus. In some embodiments, the elastic modulus of the elasticpolymeric component ranges between about 0.1 MPa and about 30 MPa. Insome embodiments, the elastic modulus of the elastic polymeric componentis at least about 0.1 MPa, at least about 0.2 MPa, at least about 0.3MPa, at least about 0.5 MPa, at least about 1 MPa, at least about 2 MPa,at least about 5 MPa, at least about 10 MPa, at least about 20 MPa, orat least about 25 MPa. In certain embodiments, the elastic modulus ofthe elastic polymeric component up to and including about 30 MPa, up toabout 25 MPa, up to and including about 20 MPa, up to and includingabout 10 MPa, up to and including about 5 MPa, up to and including about2 MPa, up to and including about 1 MPa, up to and including about 0.5MPa, up to and including about 0.3 MPa, or up to and including about 0.2MPa. Any and all closed ranges that have endpoints within any of theabove referenced ranges are also possible (e.g., between about 0.1 MPaand about 30 MPa, between about 0.3 MPa and about 10 MPa). Other rangesare also possible. Those skilled in the art would be capable ofselecting suitable methods for determining the elastic modulus of apolymeric component including, for example, tensile mechanicalcharacterization under ASTM D638 and/or compressive mechanicalcharacterization under ASTM D575.

In some embodiments, the elastic polymeric component undergoes arelatively low amount of creep during mechanical deformation. Forexample, in certain embodiments, the elastic polymeric component has aminimum creep rate of less than or equal to about 0.3 mm/mm/hr, lessthan or equal to about 0.2 mm/mm/hr, less than or equal to about 0.1mm/mm/hr, less than or equal to about 0.08 mm/mm/hr, less than or equalto about 0.05 mm/mm/hr, less than or equal to about 0.03 mm/mm/hr, orless than or equal to about 0.02 mm/mm/hr. In certain embodiments, theelastic polymeric component has a minimum creep rate of at least about0.01 mm/mm/hr, at least about 0.02 mm/mm/hr, at least about 0.03mm/mm/hr, at least about 0.05 mm/mm/hr, at least about 0.08 mm/mm/hr, atleast about 0.1 mm/mm/hr, or at least about 0.2 mm/mm/hr. Any and allclosed ranges that have endpoints within any of the above referencedranges are also possible (e.g., between about 0.01 mm/mm/hr and about0.3 mm/mm/hr, between about 0.02 mm/mm/hr and about 0.1 mm/mm/hr,between about 0.02 mm/mm/hr and about 0.05 mm/mm/hr, between about 0.05mm/mm/hr and about 0.3 mm/mm/hr). Other ranges are also possible.Minimum creep rate can be determined, in some embodiments, according toASTM D-638. Briefly, a sheet of the elastic polymeric material isprepared, as described below, and cut into a standard dumbbell die. Thespecimens can be loaded into grips of an Instron testing machine and thegauge length measured using a digital micrometer. A substantiallyconstant stress corresponding to 30% of the ultimate tensile strength ofeach material may be applied to the specimens for 60 min at constanttemperature (e.g., room temperature) and the creep (in mm/mm) versustime (in hours) can be plotted. The minimum creep rate is the slope ofthe creep vs. time curve prior to secondary creep.

Those skilled in the art given the guidance and teaching of thisspecification would be capable of determining suitable methods fortuning the mechanical properties (e.g., elastic modulus, creep behavior)of the elastic polymeric component by, for example, varying the molarratios of monomeric and/or polymeric units (e.g., increasing the amountof high molecular weight polycaprolactone or other polymers used in theelastic polymeric component), varying polymer cross-linking density,varying the concentration of cross-linking agents used in the formationof the polymer, varying the crystallinity of the polymer (e.g., byvarying the ratio of crystalline and amorphous regions in the polymer)and/or the use of additional or alternative materials (e.g.,incorporating materials such as bis(isocyanatomethyl)-cyclohexane).

In some embodiments, the elastic polymeric component does notsubstantially swell in the presence of biological fluids such as blood,water, bile, gastric fluids, combinations of these, or the like. In someembodiments, the elastic polymer component swells between about 0.01 vol% and about 10 vol % in a biological fluid as compared to the volume ofthe elastic polymer component in the dry state (e.g., at atmosphericconditions and room temperature). For example, in certain embodiments,the elastic polymeric component swells by less than about 10 vol %, lessthan about 5 vol %, less than about 2 vol %, or less than about 1 vol %in a non-stirred, gastric fluid or simulated gastric fluid atphysiological temperature as compared to the volume of the elasticpolymeric component in the dry state (e.g., at atmospheric conditionsand room temperature).

In some cases, the residence structure swells by less than about 10 vol%, less than about 5 vol %, less than about 2 vol %, or less than about1 vol % in a non-stirred, gastric fluid or simulated gastric fluid atphysiological temperature as compared to the volume of the residencestructure in the dry state (e.g., at atmospheric conditions and roomtemperature). Those skilled in the art would be capable of selectingsuitable methods for determining the amount of swelling of an elasticpolymeric component or structure based upon the teachings of thisspecification including, for example, measuring the volume of theelastic polymeric component or structure in the dry state at atmosphericconditions and room temperature, submerging the elastic polymericcomponent or structure in the non-stirred, gastric fluid or simulatedgastric fluid at physiological temperature and measuring the percentchange in volume of the component after about 60 minutes. The volume ofthe structure may be determined by, for example, fluid displacementmethods known in the art and/or by 3D scanning technology.

The elastic polymeric component is preferably biocompatible. The term“biocompatible,” as used in reference to a polymeric component, refersto a polymer that does not invoke a substantial adverse reaction (e.g.,deleterious immune response) from an organism (e.g., a mammal), a tissueculture or a collection of cells, or invokes only a reaction that doesnot exceed an acceptable level. In some embodiments, the elasticpolymeric component comprises polymers, networks of polymers, and/ormulti-block combinations of polymer segments, that may comprise polymersor polymer segments that are for example: polyesters—such as includingbut not limited to, polycaprolactone, poly(propylene fumarate),poly(glycerol sebacate), poly(lactide), poly(glycol acid),poly(lactic-glycolic acid), polybutyrate, and polyhydroxyalkanoate;polyethers—such as including but not limited to, poly(ethylene oxide)and poly(propylene oxide); polysiloxanes—such as including but notlimited to, poly(dimethylsiloxane); polyamides—such as including but notlimited to, poly(caprolactam); polyolefins—such as including but notlimited to, polyethylene; polycarbonates—such as including but notlimited to poly(propylene oxide); polyketals; polyvinyl alcohols;polyoxetanes; polyacrylates/methacrylates—such as including but notlimited to, poly(methyl methacrylate) and poly(ethyl-vinyl acetate);polyanhydrides; and polyurethanes. In some embodiments, the polymer iscross-linked. In some embodiments, the elastic polymeric componentcomprises a polymer composite comprising two or more chemically similarpolymers or two or more chemically distinct polymers. In an exemplaryembodiment, the elastic polymeric component comprises an isocyanatecross-linked polyurethane generated from low molecular weight monomerssuch as polycaprolactone. In some such embodiments, the low molecularweight monomers comprise one or more hydroxyl functional groups (e.g., adiol, a triol)

In certain embodiments, the elastic polymeric component comprises anenteric polymer such as an enteric elastomer. Enteric polymers andenteric elastomers are described in more detail, below.

According to some embodiments, a retention structure is configured toload relatively high levels (e.g., masses) of one or more activesubstances, such as therapeutic, diagnostic, and/or enhancement agents.In some embodiments, the structure is formed from one or more of avariety of materials which a have desirable properties for controlledactive substance loading and release, including, but not limited topolycaprolactone (PCL), poly(ethylene-co-vinyl acetate), andpolyethylene glycol (PEG). For example, in some embodiments, theloadable polymeric component is a polymeric component configured to loadrelatively high levels of the active substances and configured to havedesirable properties for controlled active substance loading andrelease. In some embodiments, the loadable polymeric component comprisesa drug-loadable polymer matrix. In an exemplary embodiment, the loadablepolymeric component comprises polycaprolactone. Polycaprolactone is adegradable polyester (degradable by hydrolysis of ester linkages underphysiological conditions) with a relatively low melting point of around60° C. In some embodiments, the loadable polymeric component isselectively degradable under a particular set of conditions (e.g., at aparticular range of pH and/or temperatures). In certain embodiments, theloadable polymeric component is biodegradable (e.g., in vivo.)

In some embodiments, the loadable polymeric component is configured toload relatively high levels of the active substances and/or comprises adrug loadable polymer matrix. For example, in certain embodiments, thestructure comprises the loadable polymeric component in amount of atleast about 60 wt %, at least about 70 wt % at least about 80 wt %, atleast about 90 wt %, or at least about 93 wt % of the total structureweight. In some embodiments, the structure comprises the loadablepolymeric component in an amount of up to and including about 95 wt %,up to and including about 93 wt %, up to and including about 90 wt %, upto and including about 80 wt %, or up to and including about 70 wt % ofthe total structure weight. Any and all closed ranges that haveendpoints within any of the above-referenced ranges are also possible(e.g., between about 60 wt % and about 95 wt %). For example, in someembodiments, between about 60 wt % and about 95 wt % of the structurecomprises a polymeric component capable and configured to loadrelatively high levels of active substances and/or therapeutic agents.The presence of a loadable polymeric component having the ability toload relatively high levels of active substances in an amount greaterthan about 60 wt % (e.g., greater than about 80 wt %, greater than about90 wt %) of the overall structure offers several advantages structureincluding, for example, the ability to release the active substance(e.g., therapeutic agent) over relatively long periods of time (e.g., atleast about 24 hours, at least about 48 hours, at least about 7 days, atleast about 1 month) from the structure, and/or the ability to tune therelease rate and/or duration of release of the active substance.

Several screening tests may be used to select suitable materials for useas the loadable polymeric component. For example, the loadable polymericcomponent may be selected such that the loadable polymeric component hasa flexural moduli greater than about 100 MPa, greater than about 120MPa, greater than about 150 MPa, or greater than about 200 MPa. In someembodiments, the loadable polymeric component has a flexural modulusless than or equal to about 250 MPa, less than or equal to about 200MPa, less than or equal to about 150 MPa, or less than or equal to about120 MPa. Any and all closed ranges that have endpoints within any of theabove referenced ranges are also possible (e.g., between about 100 MPaand about 250 MPa). Other ranges are also possible. Those skilled in theart would be capable of selecting suitable methods for determining theflexural moduli of a polymeric component including, for example,plotting the flexural stress versus strain and taking the slope of thelinear portion of the curve. The flexural moduli of the loadablepolymeric component may be selected to impart desirable features to thestructure including, for example, the ability to fold and/or bend suchthat the structure can be encapsulated without breaking and/or theability to withstand compressive forces such as those within the gastriccavity.

In certain embodiments, the loadable polymeric component may be selectedto have a flexural strength of at least about 10 MPa. For example, insome embodiments, the loadable polymeric component has a flexuralstrength of at least about 10 MPa, at least about 15 MPa, at least about20 MPa, at least about 30 MPa, or at least about 40 MPa. In certainembodiments, the loadable polymeric component has a flexural strength ofless than or equal to about 50 MPa, less than or equal to about 40 MPa,less than or equal to about 30 MPa, less than or equal to about 20 MPa,or less than or equal to about 15 MPa. Any and all closed ranges thathave endpoints within any of the above referenced ranges are alsopossible (e.g., between about 10 MPa and about 50 MPa). Other ranges arealso possible. Those skilled in the art would be capable of selectingsuitable methods for determining the flexural strength of the loadablepolymeric component including, for example, determining the flexuralstress at failure of the polymeric material. The flexural strength ofthe loadable polymeric component may be selected to impart desirablefeatures to the structure including, for example, the ability to foldand/or bend such that the structure can be encapsulated without breakingand/or the ability to withstand compressive forces such as those withinthe gastric cavity.

The loadable polymeric component materials may be selected such thatthey maintain their mechanical properties over a residence time period(e.g., during the release of the active substance and/or duringresidence in a body cavity). Residence time periods are described inmore detail, below. In some embodiments, the loadable polymericcomponent materials are selected such that the structure may be retainedwithin a cavity located internally of the subject (e.g., a gastriccavity) for at least 24 hours, at least 48 hours, at least one week, atleast one month, or at least one year. In certain embodiments, theloadable polymeric component materials are selected such that thestructure may be retained within a cavity location internally of thesubject for up to and including about 2 years, up to and including about1 year, up to and including about 1 month, up to and including about 1week, or up to and including about 48 hours. Any and all closed rangesthat have endpoints within any of the above-referenced ranges are alsopossible (e.g., between about 24 hours and about 2 years, between about48 hours and about 2 years, between about 1 week and about 1 year).Other ranges are also possible.

In certain embodiments, the loadable polymeric component is selectedsuch that the materials stabilize an active substance (e.g., atherapeutic agent) loaded into the component in physiologicalenvironments such as the acidic environment of the stomach for thedesired duration of retention.

In some embodiments, one or more polymeric components and/or one or morelinkers may comprise a food grade cross-linked (FGC) polymer. Forexample, in certain embodiments, the loadable polymeric componentcomprises a food grade catalyst catalyzed polymer. The use of a foodgrade cross-linked polymer offers several advantages over non-food gradepolymers including easier FDA approval, low cytotoxicity, and/or areduced need (or substantially no need) to remove toxic catalysts afterpolymerization. In some embodiments, the food grade cross-linked polymercomprises food grade ingredients cross-linked and/or polymerized using afood grade catalyst. Food grade cross-linked polymers generally may haveadvantageous combinations of properties including mechanical strength,biocompatibility and/or moldability. In some cases, the FGC polymeradvantageously can provide controlled release of the therapeutic agent,while comprising little to no potentially harmful auxiliary materials(e.g., solvents, catalysts, excipients) which, in some cases, may betoxic agents. In some embodiments, the FGC polymer is formed by thereaction of one or more monomers in the presence of a food gradecatalyst. The use of food grade catalysts to form FGC polymers can offerseveral advantages including, for example, the formation of componentswhich contain primarily (or only) FDA approved ingredients, andbiocompatibility. In certain embodiments, the FGC polymer comprisesester bonds such that, for example, the FGC polymer is degradable underphysiological conditions. Advantageously, the FGC polymer may comprise apolymeric material (e.g., a thermoset polymeric material) having thestrength and integrity of epoxy resins, the biomedical applicability ofhydrogels, and/or the moldability of vitrimers.

In some embodiments, the FGC polymer is cross-linked. In certainembodiments, the FGC polymer is substantially amorphous. In oneembodiment, the FGC polymer is useful as a loadable polymeric componentof a retention structure and is a derived from oligomeric or polymericstrands or chains which have undergone crosslinking via reactions thatdo not preclude inclusion of sensitive therapeutics (e.g., activesubstances may be loaded and released directly into the FGC polymer).The FGC polymer may be softer than conventional hardened resins and maybe characterized by a lower Young's modulus and crosslinking densitythan conventional hardened resins. In certain embodiments, in contrastto a shape memory polymer which generally returns to its original formafter it has been stretched or otherwise stressed, the FGC polymer mayremain fixed in its new shape after it has been molded into a newposition.

In some embodiments, the FGC polymer is formed by the reaction of two ormore polyfunctional monomers (e.g., a first polyfunctional monomer and asecond polyfunctional monomer). In certain embodiments, the FGC polymeris formed by the reaction of two or more, three or more, four or more,or five or more polyfunctional monomers. In some embodiments, eachpolyfunctional monomer comprises a reactive functional group. In certainembodiments, two or more reactive functional groups may form a covalentbond with one another. For example, in some cases, the reaction of afirst reactive functional group and a second reactive functional groupforms a covalent bond between the first reactive functional group andthe second reactive functional group. In other embodiments, the reactionbetween two or more reactive functional groups is a Michael-addition. Inother embodiments, the reaction between two or more reactive functionalgroups is a cycloaddition reaction, especially a Diels-Alder reaction.

In some embodiments, one or more polyfunctional monomers isbifunctional. In certain embodiments, one or more polyfunctionalmonomers is trifunctional. In some cases, one or more polyfunctionalmonomers may be tetrafunctional, pentafunctional, hexafunctional, orhave higher orders of functionality. In a particular embodiments, theFGC polymer is formed by the reaction of one or more bifunctionalmonomers and one or more trifunctional monomers.

In one embodiment, the FGC polymer may be represented by Formula (I).

A-B

_(n)  Formula (I).wherein A is derived from at least one polyfunctional monomer containingat least two reactive functional groups, and B is derived from at leastone polyfunctional monomer containing at least two reactive functionalgroups, and wherein the compound of Formula (I) comprises crosslinkedbonds. For example, in a particular embodiment, the FGC polymercomprising the structure as in Formula (I) is formed by the reaction ofa first polyfunctional monomer comprising two reactive functional groupsand a second polyfunctional comprising three reactive functional groups.In another embodiment, the FGC polymer comprising the structure as inFormula (I) is formed by the reaction of a first polyfunctional monomercomprising two reactive functional groups, a second polyfunctionalmonomer different than the first polyfunctional monomer comprising tworeactive functional groups, and a third polyfunctional monomercomprising three reactive functional groups. In some such embodiments,the reactive functional groups of the first polyfunctional monomer maybe the same or different as the reactive functional groups of the secondpolyfunctional monomer and/or the third polyfunctional monomer. Forexample, the reactive groups of the first polyfunctional monomer mayreact with (and form a covalent bond with) the reactive groups of thesecond polyfunctional monomer and/or the third polyfunctional monomer.

In some embodiments, one or more polyfunctional monomers contain anoligomeric moiety. In certain embodiments, the FGC polymer of Formula(I) is further characterized by the presence of at least two reactivegroups capable of forming a crosslink bond.

In certain embodiments, the compound of Formula (I) is prepared bycombining two or more polyfunctional monomers, and then incubating themixture at a temperature sufficient to initiate polymerization to reachthe gel point. In some embodiments, the two or more polyfunctionalmonomers are combined in the presence of a catalyst. In certainembodiments, two or more polyfunctional monomers are combined in thepresence of a subunit compound, in the presence of an active substance,or both.

In some embodiments, the polyfunctional monomer has a structure as inFormula (II):Q¹-L-Q²  (II)wherein Q¹ and Q² are the same or different and a reactive functionalgroup and L has a structure as in Formula (III):

wherein

indicates a point of connection to Q¹ and Q².

In some embodiments, the polyfunctional monomer has a structure as in:

wherein Q¹, Q², and Q³ are the same or different and a reactivefunctional group and L has a structure as in Formula (III).In some embodiments, X¹, X², and X³ are the same or different and areabsent or selected from the group consisting of (CR¹R²)_(m), aheteroatom, an alkenyl, an alkynyl, a cycloalkyl, an aryl, aheterocyclic group, a heteroaryl group, and an oligomeric group. Incertain embodiments, X¹, X², and/or X³ are absent.

In certain embodiments, m is zero or any integer. For example, in someembodiments, m is 0. In certain embodiments, m is 1-3, 2-4, 3-6, 4-8,5-10, 8-16, 12-24, 20-30, 25-50, 40-60, 50-100, 75-150, 125-200,150-300, 250-500, 400-600, 500-800, or 750-1500. In some cases, m is1-3. In certain embodiments, m is 2-4. In some cases, m is 4-8. In someembodiments, m is 8-16. The value of m may be selected to impart certainproperties in the FGC polymer (e.g., crosslink density, Young's elasticmodulus).

In some embodiments, y is zero or any integer. For example, in someembodiments, y is 0. In certain embodiments, y is 1-3, 2-4, 3-6, 4-8,5-10, 8-16, 12-24, 20-30, 25-50, 40-60, 50-100, 75-150, 125-200,150-300, 250-500, 400-600, 500-800, or 750-1500. In some cases, y is1-3. In certain embodiments, y is 2-4. In some cases, y is 4-8. In someembodiments, y is 8-16. The value of y may be selected to impart certainproperties in the FGC polymer (e.g., crosslink density, Young's elasticmodulus).

In certain embodiments, z is zero or any integer. For example, in someembodiments, z is 0. In certain embodiments, z is 1-3, 2-4, 3-6, 4-8,5-10, 8-16, 12-24, 20-30, 25-50, 40-60, 50-100, 75-150, 125-200,150-300, 250-500, 400-600, 500-800, or 750-1500. In some cases, z is1-3. In certain embodiments, z is 2-4. In some cases, z is 4-8. In someembodiments, z is 8-16. The value of z may be selected to impart certainproperties in the FGC polymer (e.g., crosslink density, Young's elasticmodulus).

In a particular embodiment, m+y+z is zero. In certain embodiments, m+y+zis 1. In some cases, m+y+z is an integer and is 2 or greater.

In some embodiments, each R¹ and R² are the same or different and areselected from the group consisting of hydrogen, an aliphatic group, ahalogen, a hydroxyl, a carbonyl, a thiocarbonyl, an oxo, an alkoxy, anepoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, anamino, an amido, an amidine, an imine, a cyano, a nitro, an azido, athiol, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido,a sulfonyl, a cycloalkyl, a heterocyclyl, an aralkyl, and an aromatic orheteroaromatic or a Michael acceptor, wherein any two or more R¹ and R²groups may be bonded together so as to form a ring system. In certainembodiments, each R¹ and/or R² may be Q³ (i.e. a reactive functionalgroup).

In an exemplary embodiment, the polyfunctional monomer has the structureas in Formula (IV):

wherein L is as described above. In another exemplary embodiments, thepolyfunctional monomer has the structure as in:

wherein L is as described above. In yet another exemplary embodiment,the polyfunctional monomer has a structure as in Formula (V) or Formula(VI):

wherein L is described above. In some embodiments, the FGC polymer isformed by the reaction of a first polyfunctional monomer having astructure as in Formula (IV) with a second polyfunctional monomer havinga structure as in Formula (V) or Formula (VI).

Polyfunctional monomers described herein may comprise at least two, atleast three, at least four, or at least five reactive functional groups.For example, in some embodiments, Q¹, Q², and Q³ may be the same ordifferent and an electrophilic functional groups or a nucleophilicfunctional group.

In some embodiments, one or more reactive groups (e.g., Q¹, Q², and/orQ³) is an electrophilic functional groups. For example, a monomer maycomprise at least two, at least three, at least four, or at least fiveelectrophilic functional groups. Non-limiting examples of suitableelectrophilic functional groups include alkenes, alkynes, esters (e.g.,N-hydroxysuccinimide ester), acrylates, methacrylates, acyl halides,acyl nitriles, alkyl halides, aldehydes, ketones, alkyl sulfonates,anhydrides, epoxides, haloacetamides, aziridines, and diazoalkanes.

In certain embodiments, one or more reactive functional groups (e.g.,Q¹, Q², and/or Q³) is a nucleophilic functional groups. For example, amonomer may comprise at least two, at least three, at least four, or atleast five nucleophile reactive functional groups. Non-limiting examplesof suitable nucleophilic functional groups include alcohols, amines,anilines, phenols, hydrazines, hydoxylamines, carboxylic acids, alkoxidesalts, alkenes, thiols, and glycols.

The polyfunctional monomers described herein may comprise at least oneelectrophilic functional group and at least one nucleophilic functionalgroup. For example, in an exemplary embodiment, the first polyfunctionalmonomer comprises both an electrophilic functional group and anucleophilic functional group. In certain embodiments, the firstpolyfunctional monomer comprises two or more electrophile functionalgroups and the second polyfunctional monomer comprises two or morenucleophile functional groups.

In some cases, the reaction of an electrophilic functional group and anucleophilic functional group form a bioresponsive bond such as an esterbond, an ether bond, an amide bond, an amine bond, or a thioether bond.For example, in certain embodiments, the FGC polymer comprises an esterbond formed by the reaction of an electrophilic functional group and anucleophilic functional group. In some embodiments, the FGC polymercomprises an ether bond formed by the reaction of an electrophilicfunctional group and a nucleophilic functional group. Other bonds arealso possible.

In some embodiments the FGC polymer is formed by the reaction of two ormore polyfunctional monomers and an additional monomeric unit. In someembodiments, the additional monomeric unit comprises a compoundcontaining one or more carboxylic acid derivatives. In some embodiments,the additional monomeric unit is a single compound containing at leastone ester, amide or thioester group, or a mixture of compoundscontaining at least one ester, amide or thioester. In certainembodiments, the additional monomeric unit is a compound containing alactone, lactam or thiolactone group. In certain embodiments, theadditional monomeric unit is a naturally occurring lactone or lactam. Inanother embodiment, the additional monomeric unit lactone-containing orlactam-containing compound selected from the FDA's “Generally Recognizedas Safe” Substances database and/or listed in 21 C.F.R. § 182. Incertain embodiments, the additional monomeric unit is selectedγ-decalactone, δ-decalactone, ω-pentadecalactone, caprolactam, andmixtures thereof.

In certain embodiments of the invention, the additional monomeric unitdoes not contain a primary or secondary amine moiety.

In some embodiments, the molar ratio of the first polyfunctional monomer(e.g., comprising electrophilic reactive groups) to a mixture ofadditional polyfunctional monomers (e.g., comprising nucleophilicreactive groups) and/or additional monomeric units ranges between about10:1 and about 1:10. In an exemplary embodiment, the molar ratio of thefirst polyfunctional monomer to a mixture of additional polyfunctionalmonomers and/or monomeric units is about 1:1. In certain embodiments,the molar ratio of first polyfunctional monomer to a mixture ofadditional polyfunctional monomers and/or monomeric units is at lessthan about 10:1, less than about 8:1, less than about 6:1, less thanabout 4:1, less than about 2:1, less than about 1.5:1, less than about1:1, less than about 1.5:1, less than about 1:2, less than about 1:4,less than about 1:6, or less than about 1:8. In some embodiments, themolar ratio of first polyfunctional monomer to a mixture of additionalpolyfunctional monomers and/or monomeric units is greater than or equalto about 1:10, greater than or equal to about 1:8, greater than or equalto about 1:6, greater than or equal to about 1:4, greater than or equalto about 1:2, greater than or equal to about 1:1.5, greater than orequal to about 1:1, greater than or equal to about 1.5:1, greater thanor equal to about 2:1, greater than or equal to about 4:1, greater thanor equal to about 6:1, or greater than or equal to about 8:1. Any andall closed ranges that have endpoints within any of the above-referencedranges are also possible (e.g., between about 10:1 and about 1:10,between about 1:4 and about 4:1, between about 1:2 and about 2:1).

In some such embodiments, the second polyfunctional monomer is presentin the mixture of additional polyfunctional monomers and/or monomericunits in an amount of at least about 10 mol %, at least about 20 mol %,at least about 25 mol %, at least about 50 mol %, at least about 75 mol%, at least about 90 mol %, or at least about 99 mol %. In certainembodiments, the second polyfunctional monomer is present in the mixtureof additional polyfunctional monomers and/or monomeric units in anamount of less than or equal to about 99.9 mol %, less than or equal toabout 99 mol %, less than or equal to about 90 mol %, less than or equalto about 75 mol %, less than or equal to about 50 mol %, less than orequal to about 25 mol %, or less than or equal to about 20 mol %. Anyand all closed ranges that have endpoints within any of theabove-referenced ranges are also possible (e.g., between about 25 mol %and about 99.9 mol %). Other ranges are also possible.

As described above, in some embodiments, two or more polyfunctionalmonomers are combined (i.e. reacted) in the presence of a catalyst.

In some embodiments, the catalyst is a nucleophile. In certainembodiments, the catalyst is a base (e.g., a mild base, a weak base). Incertain embodiments, the catalyst is a metal salt. In some embodiments,the catalyst is a sulfate salt of zinc such as ZnSO₄ and hydratesthereof.

In some embodiments, the catalyst is selected from catalysts listed inFDA's “Generally Recognized as Safe” Substances database and/or listedin 21 C.F.R. § 182. In certain embodiments, the catalyst is food gradeand/or food derived catalyst.

In certain embodiments, the catalyst is an organic amine. In someembodiments, the catalyst is a tertiary amine. In some cases, thetertiary amine catalyst does not contain any amino N—H or NH₂ functionalgroups.

In some embodiments, the catalyst is an alkaloid compound. In certainembodiments, the catalyst is a purine base. Non-limiting examples ofpurine bases include purine, adenine, guanine, hypoxanthine, xanthine,theobromine, caffeine, uric acid and isoguanine. In an exemplaryembodiment, the catalyst is caffeine.

The use of a food grade catalyst such as caffeine may offer certainadvantages over traditional catalysts including easier FDA approval, lowcytotoxicity, and/or a reduced need (or substantially no need) to removethe catalyst after polymerization.

In some embodiments, the catalyst (e.g., food grade catalyst) is presentin the FGC polymer after the formation of the FGC polymer in an amountranging between 0.01 mol % and about 25 mol %. In some embodiments, theFGC polymer comprises substantially no catalyst after the formation ofthe FGC polymer. In certain embodiments, the catalyst is present in theFGC polymer after the formation of the FGC polymer in an amount of atleast about 0.01 mol %, at least about 0.05 mol %, at least about 0.1mol %, at least about 0.5 mol %, at least about 1 mol %, at least about2 mol %, at least about 5 mol %, at least about 10 mol %, or at leastabout 20 mol %. In certain embodiments, the catalyst is present in theFGC polymer after the formation of the FGC polymer in an amount of lessthan or equal to about 25 mol %, less than or equal to about 20 mol %,less than or equal to about 10 mol %, less than or equal to about 5 mol%, less than or equal to about 2 mol %, less than or equal to about 1mol %, less than or equal to about 0.5 mol %, less than or equal toabout 0.1 mol %, or less than or equal to about 0.05 mol %. Any and allclosed ranges that have endpoints within any of the above-referencedranges are also possible (e.g., between 1 mol % and 25 mol %, between0.01 mol % and 5 mol %). Other ranges are also possible.

As described above, in some embodiments, the FGC polymer may be formedusing three or more polyfunctional monomers. In an exemplary reaction,polypropylene oxide is reacted with citric acid, mercaptosuccinic acid,and PPO-dimethacrylate in the presence of caffeine via Michael additionto form a branched FGC polymer.

In some embodiments, the structure (e.g., the loadable polymericcomponent) is pre-loaded with an active substance such as a therapeutic,diagnostic, and/or enhancement agents. In other embodiments, thestructure (e.g., the loadable polymeric component) is loaded withtherapeutic, diagnostic, and/or enhancement agents after it is alreadyretained at a location internal to a subject, such as a gastric cavity.In some embodiments, a structure is configured to maintain stability oftherapeutic, diagnostic, and/or enhancement agents in a hostilephysiological environment (e.g., the gastric environment) for anextended duration. In further embodiments, the structure is configuredto control release of therapeutic, diagnostic, and/or enhancement agentswith low to no potential for burst release. In some embodiments, thestructure (e.g., the loadable polymeric component) is pre-loaded and/orloaded with a combination of active substances. For example, in certainembodiments, the structure comprises one or more, two or more, three ormore, or four or more active substances.

Therapeutic, diagnostic, and/or enhancement agents can be loaded intopolymeric materials and other drug delivery materials via standardmethods including, but not limited to, powder mixing, direct addition,solvent loading, melt loading, physical blending, supercritical carbondioxide assisted, and conjugation reactions such as ester linkages andamide linkages. Release of therapeutic, diagnostic, and/or enhancementagents can then be accomplished through methods including, but notlimited to, dissolution of the loadable polymeric component comprising apolymeric matrix material, degradation of the matrix material, swellingof the matrix material, diffusion of an agent, hydrolysis, and chemicalor enzymatic cleavage of conjugating bonds. In some embodiments, theactive substance is covalently bound to the polymer matrix of thepolymeric component (e.g., and is released as the polymer matrixdegrades).

In certain embodiments, the structure is constructed and arranged torelease the active substance from the loadable polymeric component(s).In certain embodiments, the active substance is designed for releasefrom the loadable polymeric component. Such embodiments may be useful inthe context of drug delivery. In other embodiments, the active substanceis permanently affixed to the loadable polymeric component. Suchembodiments may be useful in molecular recognition and purificationcontexts. In certain embodiments, the active substance is embeddedwithin the loadable polymeric component. In some embodiments, the activesubstance is associated with the loadable polymeric component viaformation of a bond, such as an ionic bond, a covalent bond, a hydrogenbond, Van der Waals interactions, and the like. The covalent bond maybe, for example, carbon-carbon, carbon-oxygen, oxygen-silicon,sulfur-sulfur, phosphorus-nitrogen, carbon-nitrogen, metal-oxygen, orother covalent bonds. The hydrogen bond may be, for example, betweenhydroxyl, amine, carboxyl, thiol, and/or similar functional groups.

According to some embodiments, the systems, structures, and methodsdescribed herein are compatible with one or more therapeutic,diagnostic, and/or enhancement agents, such as drugs, nutrients,microorganisms, in vivo sensors, and tracers. In some embodiments, theactive substance, is a therapeutic, nutraceutical, prophylactic ordiagnostic agent. The active substance may be entrapped within thepolymeric matrix or may be directly attached to one or more atoms in thepolymeric matrix through a chemical bond. In certain embodiments, theactive substance is covalently bonded to the polymeric matrix. In someembodiments, the active substance is bonded to the polymeric matrixthrough a carboxylic acid derivative. In some cases, the carboxylic acidderivative may form an ester bond with the active substance.

Agents can include, but are not limited to, any synthetic ornaturally-occurring biologically active compound or composition ofmatter which, when administered to a subject (e.g., a human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. For example, usefulor potentially useful within the context of certain embodiments arecompounds or chemicals traditionally regarded as drugs, vaccines, andbiopharmaceuticals, Certain such agents may include molecules such asproteins, peptides, hormones, nucleic acids, gene constructs, etc., foruse in therapeutic, diagnostic, and/or enhancement areas, including, butnot limited to medical or veterinary treatment, prevention, diagnosis,and/or mitigation of disease or illness (e.g., HMG co-A reductaseinhibitors (statins) like rosuvastatin, nonsteroidal anti-inflammatorydrugs like meloxicam, selective serotonin reuptake inhibitors likeescitalopram, blood thinning agents like clopidogrel, steroids likeprednisone, antipsychotics like aripiprazole and risperidone, analgesicslike buprenorphine, antagonists like naloxone, montelukast, andmemantine, cardiac glycosides like digoxin, alpha blockers liketamsulosin, cholesterol absorption inhibitors like ezetimibe,metabolites like colchicine, antihistamines like loratadine andcetirizine, opioids like loperamide, proton-pump inhibitors likeomeprazole, antiviral agents like entecavir, antibiotics likedoxycycline, ciprofloxacin, and azithromycin, anti-malarial agents, andsynthroid/levothyroxine); substance abuse treatment (e.g., methadone andvarenicline); family planning (e.g., hormonal contraception);performance enhancement (e.g., stimulants like caffeine); and nutritionand supplements (e.g., protein, folic acid, calcium, iodine, iron, zinc,thiamine, niacin, vitamin C, vitamin D, and other vitamin or mineralsupplements).

In some embodiments, the active substance is a radiopaque material suchas tungsten carbide or barium sulfate.

In certain embodiments, the active substance is one or more specifictherapeutic agents. As used herein, the term “therapeutic agent” or alsoreferred to as a “drug” refers to an agent that is administered to asubject to treat a disease, disorder, or other clinically recognizedcondition, or for prophylactic purposes, and has a clinicallysignificant effect on the body of the subject to treat and/or preventthe disease, disorder, or condition. Listings of examples of knowntherapeutic agents can be found, for example, in the United StatesPharmacopeia (USP), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic andClinical Pharmacology, McGraw-Hill/Appleton & Lange; 8th edition (Sep.21, 2000); Physician's Desk Reference (Thomson Publishing), and/or TheMerck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed(2006) following its publication, Mark H. Beers and Robert Berkow(eds.), Merck Publishing Group, or, in the case of animals, The MerckVeterinary Manual, 9th ed., Kahn, C. A. (ed.), Merck Publishing Group,2005; and “Approved Drug Products with Therapeutic Equivalence andEvaluations,” published by the United States Food and DrugAdministration (F.D.A.) (the “Orange Book”). Examples of drugs approvedfor human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331through 361, and 440 through 460, incorporated herein by reference;drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500through 589, incorporated herein by reference. In certain embodiments,the therapeutic agent is a small molecule. Exemplary classes oftherapeutic agents include, but are not limited to, analgesics,anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants,antiepileptics, antipsychotic agents, neuroprotective agents,anti-proliferatives, such as anti-cancer agents, antihistamines,antimigraine drugs, hormones, prostaglandins, antimicrobials (includingantibiotics, antifungals, antivirals, antiparasitics), antimuscarinics,anxioltyics, bacteriostatics, immunosuppressant agents, sedatives,hypnotics, antipsychotics, bronchodilators, anti-asthma drugs,cardiovascular drugs, anesthetics, anti-coagulants, inhibitors of anenzyme, steroidal agents, steroidal or non-steroidal anti-inflammatoryagents, corticosteroids, dopaminergics, electrolytes, gastro-intestinaldrugs, muscle relaxants, nutritional agents, vitamins,parasympathomimetics, stimulants, anorectics and anti-narcoleptics.Nutraceuticals can also be incorporated into the drug delivery device.These may be vitamins, supplements such as calcium or biotin, or naturalingredients such as plant extracts or phytohormones.

In some embodiments, the therapeutic agent is one or more antimalarialdrugs. Exemplary antimalarial drugs include quinine, lumefantrine,chloroquine, amodiaquine, pyrimethamine, proguanil,chlorproguanil-dapsone, sulfonamides such as sulfadoxine andsulfamethoxypyridazine, mefloquine, atovaquone, primaquine,halofantrine, doxycycline, clindamycin, artemisinin and artemisininderivatives. In some embodiments, the antimalarial drug is artemisininor a derivative thereof. Exemplary artemisinin derivatives includeartemether, dihydroartemisinin, arteether and artesunate. In certainembodiments, the artemisinin derivative is artesunate.

Active substances that contain a carboxylic acid group may be directlyincorporated into polymeric matrices that contain ester and hydroxylgroups without further modification. Active substances containing analcohol may first be derivatized as a succinic or fumaric acid monoesterand then incorporated into the polymeric matrix. Active substances thatcontain a thiol may be incorporated into olefin or acetylene-containingmatrices through a sulfur-ene reaction. In other embodiments, the one ormore agents are non-covalently associated with the polymeric matrices(e.g., dispersed or encapsulated within).

In other embodiments, the active substance is a protein or otherbiological macromolecule. Such substances may be covalently bound to thepolymeric matrix through ester bonds using available carboxylatecontaining amino acids, or may be incorporated into polymeric materialcontaining olefinic or acetylenic moieties using a thiol-ene typereaction. In some cases, the active substance comprises an aminefunctional group capable of reacting with an epoxide functional group toform an amide or ester bond. In other embodiments, the active substanceis non-covalently associated with the polymeric matrix. In some suchembodiments, the active substance may be dispersed or encapsulatedwithin by hydrophilic and/or hydrophobic forces.

In some cases, the partition coefficient of the active substance in theloadable polymeric component material can be tuned. For example, if theactive substance is hydrophobic, a hydrophobic polymeric materialbackbone may, in some cases, slow the release into aqueous solution,however, a hydrophilic polymeric material backbone should accelerate it.Additionally, a hydrophilic polymeric material backbone may, in somecases, increase the rate of water absorption into the material,expanding (e.g., swelling) the polymeric material and acceleratingrelease rate. The expansion and dissolution of the material may beincreased, in some embodiments, under conditions when free reactivegroups contain ionizable moieties that become charged in the presence ofaqueous media. In some such embodiments, as the material disintegratesdue to ionic repulsion, the rate of release of contents may be increasedvia diffusion and/or better access to cleavable bonds may be imparted.Those skilled in the art would be capable of selecting suitable methodsfor determining the partition coefficient of the active substanceincluding, for example, high performance liquid chromatography (HPLC).

The active substance may be associated with the polymeric matrix and/orpresent in the loadable polymeric component in any suitable amount. Insome embodiments, the active substance is present in the loadablepolymeric component an amount ranging between about 0.01 wt % and about50 wt % versus the total loadable polymeric component weight. In someembodiments, the active substance is present in the loadable polymericcomponent in an amount of at least about 0.01 wt %, at least about 0.05wt %, at least about 0.1 wt %, at least about 0.5 wt %, at least about 1wt %, at least about 2 wt %, at least about 3 wt %, at least about 5 wt%, at least about 10 wt %, at least about 20 wt %, at least about 30 wt%, at least about 40 wt % of the total loadable polymeric componentweight. In certain embodiments, the active substance is present in theloadable polymeric component in an amount of less than or equal to about50 wt %, less than or equal to about 40 wt %, less than or equal toabout 30 wt %, less than or equal to about 20 wt %, less than or equalto about 10 wt %, less than or equal to about 5 wt %, less than or equalto about 3 wt %, less than or equal to about 2 wt %, less than or equalto about 1 wt %, less than or equal to about 0.5 wt %, less than orequal to about 0.1 wt %, or less than or equal to about 0.05 wt %. Anyand all closed ranges that have endpoints within any of theabove-referenced ranges are also possible (e.g., between about 0.01 wt %and about 50 wt %). Other ranges are also possible.

Advantageously, certain embodiments of the loadable polymeric componentsdescribed herein may permit higher concentrations (weight percent) ofactive substances such as therapeutic agents to be incorporated ascompared to other polymers such as certain conventional hydrogels. Insome embodiments, the active substance (e.g., the active substance) maybe released from the loadable polymeric component. In certainembodiments, the active substance is released by diffusion out of theloadable polymeric component. In some embodiments, the active substanceis released by degradation of the loadable polymeric component (e.g.,biodegradation, enzymatic degradation, hydrolysis). In some embodiments,the active substance is released from the loadable polymeric componentat a particular rate. Those skilled in the art would understand that therate of release may be dependent, in some embodiments, on the solubilityof the active substance in the medium in which the loadable polymericcomponent is exposed, such as a physiological fluid such as gastricfluid. The ranges and description included related to the release and/orrate of release of the active substance is generally in reference tohydrophilic, hydrophobic, and/or lipophilic active substances insimulated gastric fluid (e.g., as defined in the United StatesPharmacopeia (USP)). Simulated gastric fluids are known in the art andthose skilled in the art would be capable of selecting suitablesimulated gastric fluids based on the teachings of this specification.

In some embodiments, between 0.05 wt % to 99 wt % of the activesubstance initially contained in a loadable polymeric component isreleased (e.g., in vivo) between 24 hours and 1 year. In someembodiments, between about 0.05 wt % and about 99.0 wt % of the activesubstance is released (e.g., in vivo) from the loadable polymericcomponent after a certain amount of time. In some embodiments, at leastabout 0.05 wt %, at least about 0.1 wt %, at least about 0.5 wt %, atleast about 1 wt %, at least about 5 wt %, at least about 10 wt %, atleast about 20 wt %, at least about 50 wt %, at least about 75 wt %, atleast about 90 wt %, at least about 95 wt %, or at least about 98 wt %of the active substance associated with the loadable polymeric componentis released from the component (e.g., in vivo) within about 24 hours,within 36 hours, within 72 hours, within 96 hours, or within 192 hours.In certain embodiments, at least about 0.05 wt %, at least about 0.1 wt%, at least about 0.5 wt %, at least about 1 wt %, at least about 5 wt%, at least about 10 wt %, at least about 20 wt %, at least about 50 wt%, at least about 75 wt %, at least about 90 wt %, at least about 95 wt%, or at least about 98 wt % of the active substance associated with thepolymeric component is released from the component (e.g., in vivo)within 1 day, within 5 days, within 30 days, within 60 days, within 120days, or within 365 days. For example, in some cases, at least about 90wt % of the active substance associated with the polymeric component isreleased from the component (e.g., in vivo) within 120 days.

In some embodiments, the active substance is released from the loadablepolymeric material at a particular initial average rate as determinedover the first 24 hours of release (the “initial rate”) (e.g., releaseof the active substance at the desired location internally of thesubject, such as an internal cavity). In certain embodiments, the activesubstance is released at an average rate of at least about 1%, at leastabout 2%, at least about 5%, least about 10%, at least about 20%, atleast about 30%, least about 50%, at least about 75%, at least about80%, at least about 90%, at least about 95%, or at least about 98% ofthe initial average rate over a 24 hour period after the first 24 hoursof release. In some embodiments, the active substance is released at anaverage rate of less than or equal to about 99%, less than or equal toabout 98%, less than or equal to about 95%, less than or equal to about90%, less than or equal to about 80%, less than or equal to about 75%,less than or equal to about 50%, less than or equal to about %, lessthan or equal to about 30%, less than or equal to about 20%, less thanor equal to about 10%, less than or equal to about 5%, or less than orequal to about 2% of the initial average rate over a 24 hour periodafter the first 24 hours of release. Any and all closed ranges that haveendpoints within any of the above referenced ranges are also possible(e.g., between about 1% and about 99%, between about 1% and about 98%,between about 2% and about 95%, between about 10% and about 30%, betweenabout 20% and about 50%, between about 30% and about 80%, between about50% and about 99%). Other ranges are also possible.

The active substance may be released at an average rate over at leastone selected continuous 24 hour period at a rate of between about 1% andabout 99% of the initial rate between 48 hours and about 1 year (e.g.,between 48 hours and 1 week, between 3 days and 1 month, between 1 weekand 1 month, between 1 month and 6 months, between 3 months and 1 year,between 6 months and 2 years) after the initial release.

For example, in some cases, the active substance may be released at arate of between about 1% and about 99% of the initial rate on the secondday of release, the third day of release, the fourth day of release, thefifth day of release, the sixth day of release, and/or the seventh dayof release.

In certain embodiments, burst release of an active substance from theloadable polymeric component is generally avoided. In an illustrativeembodiment, in which at least about 0.05 wt % of the active substance isreleased from the loadable polymeric component within 24 hours, betweenabout 0.05 wt % and about 99 wt % is released during the first day ofrelease (e.g., at the location internally of the subject), and betweenabout 0.05 wt % and about 99 wt % is released during the second day ofrelease. Those skilled in the art would understand that the activesubstance may be further released in similar amounts during a third day,a fourth day, a fifth day, etc. depending on the properties of theloadable polymeric component and/or the active substance.

In certain embodiments, the active substance may be released with apulse release profile. For example, in some embodiments, the activesubstance may be released on the first day after administration andduring another 24 hour period such as starting during the third day, thefourth day, or the fifth day, but is not substantially released on otherdays. Those skilled in the art would understand that other days and/orcombinations of pulsing and continuous release are also possible.

The active substance may be released at a relatively constant averagerate (e.g., a substantially zero-order average release rate) over a timeperiod of at least about 24 hours. In certain embodiments, the activesubstance is released at a first-order release rate (e.g., the rate ofrelease of the active substance is generally proportional to theconcentration of the active substance) of a time period of at leastabout 24 hours.

In some embodiments, at least a portion of the active substance loadedinto the structure is released continuously (e.g., at varying rates)over the residence time period of the structure. Residence time periodsare described in more detail, below.

As described above, in some embodiments, the one or more polymericcomponents are coupled together via one or more linkers. Those skilledin the art would understand that the term coupled generally refers to aphysical linkage (which may, for example, be effected by physical and/orchemical bond forces) connecting two or more components. In someembodiments, the first (elastic) polymeric component may be coupled withthe second (loadable) polymeric component via an adhesive, by chemicalinteractions, and/or by interpenetrating (e.g., entangled) polymerchains. For example, in some embodiments, a polymer backbone of thefirst polymeric component and a polymer backbone the second polymericcomponent are coupled via a bond such as an ionic bond, a covalent bond,a hydrogen bond, Van der Waals interactions, and the like. The covalentbond may be, for example, carbon-carbon, carbon-oxygen, oxygen-silicon,sulfur-sulfur, phosphorus-nitrogen, carbon-nitrogen, metal-oxygen, orother covalent bonds. The hydrogen bond may be, for example, betweenhydroxyl, amine, carboxyl, thiol, and/or similar functional groups.

In certain embodiments, the elastic polymeric component and the loadablepolymeric component are coupled via an adhesive (e.g., a biocompatibleadhesive). Non-limiting examples of suitable adhesives includebiocompatible polyurethanes, cyanoacrylates, or the like.

In some embodiments, the polymer material of the elastic polymericcomponent and polymer material of the loadable polymeric component mayinterpenetrate and/or entangle such that the elastic polymeric componentand the loadable polymeric component are coupled.

In some embodiments, the elastic polymeric component and a loadablepolymeric component are coupled via a linker. According to someembodiments, the structure is configured to degrade, dissolve, and/ordisassociate into one or more forms configured for passing through agastrointestinal tract. In some embodiments, the structure comprises oneor more linkers designed for controlled and/or tunable degradation.According to some embodiments, one or more linkers are attached toand/or incorporated into a structure to separate in a modular fashionthe function of delivering therapeutic, diagnostic, and/or enhancementagents from controlling (e.g., triggering) and/or tuning degradation.Referring again to FIGS. 1B-1C, a first polymeric component 110 and asecond polymeric component 120 are coupled via linker 130. In certainembodiments, two or more elastic polymeric components are coupledtogether via a linker. In some embodiments, two or more loadablepolymeric components are coupled together via a linker. In someembodiments, the linker is embedded within a polymeric component. Forexample, in certain embodiments, the linker is embedded within anelastic polymeric component. In some cases, the linker may be embeddedwithin a loadable polymeric component. In some such embodiments, thelinker may degrade at a desired time and/or under desired conditionssuch that the elastic polymeric component or loadable polymericcomponent breaks apart.

The structure may comprise one or more, two or more, or three or moretypes of linkers. For example, in an illustrative embodiment, thestructure comprises a first linker configured for degradation at a firstaverage degradation rate and a second linker configured for degradationat a second average degradation rate under the same conditions. Incertain embodiments, the linker degradation is pH dependent. In anotherillustrative embodiment, the structure comprises a first linkerconfigured for degradation under a first set of physiological conditions(e.g., in (1) acidic pH such as in the stomach or, (2) alternatively, inrelatively neutral pH such as in the intestines, etc.) and a secondlinker configured for degradation under a second set of physiologicalconditions different than the first set of physiological conditions(e.g., (1) in relatively neutral pH such as in the intestines, or,alternatively, (2) acidic pH such as in the stomach, etc.). In someembodiments, the second linker is not configured for substantialdegradation under the first set of conditions, thereby enablingselectable and partial degradation of the structure under selectcondition and/or in select locations within a subject (e.g., differentpositions along the G.I. track.) For example, in some cases, the secondlinker is not substantially degradable at a first physiologicalcondition (e.g., in acidic pH such as in the stomach) and is configuredfor degradation at a second physiological condition different than thefirst set of physiological conditions.

The term physiological condition generally refers to a set of conditionsof the external or internal milieu that occurs in an organism orcellular system (e.g., in contrast to laboratory conditions). Forexample, in some cases, a physiological condition ranges in temperaturebetween about 20° C. and about 40° C. (e.g., between about 35° C. andabout 38° C.) and/or atmospheric pressure of about 1 atm. In certainembodiments, the physiological conditions are that of an internal organsuch as the stomach, intestines, bladder, lungs, and/or heart. Thelinker may be selected such that the linker dissolves, degrades,mechanically weakens, and/or mechanically separates from at least one ofthe one or more polymeric components after a particular residence timeperiod. The term residence time period generally refers to the length oftime during which the structure (or a component of the structure)described herein is resided at a location internally of a subject asmeasured from the time initially present in the location internally ofthe subject to the time at which the structure (or such component of thestructure being referenced) no longer resides at the location internallyof the subject due to, for example, degradation, dissolution, and/orexit of the structure or such component(s) of the structure beingreferenced structure from the location internally of the subject. In anillustrative embodiment, the structure may be orally administered suchthat the structure resides at a location internally of the subject suchas the stomach above the pylorus and exits through the pylorus into theintestine (e.g., after degradation of at least a portion of thestructure), where the residence time period is measured as the length oftime between when the structure initially resides in the stomach andwhen the structure (or a component of the structure being referenced)exits through the pylorus.

In some embodiments, the residence time period of at least a portion ofthe structure is at least about 24 hours, at least about 48 hours, atleast about 3 days, at 7 days, at least about 1 month, at least about 6months, or at least about 1 year. In certain embodiments, the residencetime period is less than or equal to about 2 years, less than or equalto about 1 year, less than or equal to about 6 months, less than orequal to about 1 month, less than or equal to about 7 days, less than orequal to about 3 days, or less than or equal to about 48 hours. Any andall closed ranges that have endpoints within any of the above-referencedranges are also possible (e.g., between about 24 hours and about 2years, between about 24 hours and about 1 year, between about 48 hoursand about 7 days, between about 3 days and about 1 month, between about7 days and about 6 months, between about 1 month and about 1 year).Other ranges are also possible. The linker is preferrably biocompatible.

In an exemplary embodiment, the one or more linkers are selected tomediate disassembly of the structure after, for example, delivery of anactive substance for over a desired residence time period (e.g., within24 hours, within 48 hours, within one week, within one month), andfacilitate safe passage through the lower intestinal tract of thesubject. Exit from an orifice such as the gastric cavity may be achievedthrough changes in the mechanical properties of the linker (e.g., viabiodegradation) such that the ability to resist passage through anorifice (e.g., through the pylorus) is compromised, through breakage inthe structure through designed linker failure, etc.

Several screening tests may be used to determine suitable materials foruse as linkers, including but not limited to the ability to interface(e.g., couple) with at least a surface of the one or more of thepolymeric components of the structure, possession of mechanical strengthsufficient to survive encapsulation, possession of mechanical strengthsufficient to undergo the compressive forces present in physiologicalenvironments such as the gastric environment, and/or selectivedegradation under desired times and/or conditions (e.g., pH). In someembodiments, the linker is stable within a physiological environmentsuch as the gastric environment for a period of time (e.g., a residencetime period) of at least about 24 hours, at least about 48 hours, atleast about one week, at least about one month, or least about one year.

In certain embodiments, the linker comprises a material such that, underrelatively neutral pH physiological conditions (e.g., such as those inthe duodenum), the linker can be mechanically broken (i.e. mechanicalfailure) by a tensile force less than or equal to about 2 N within lessthan or equal to about 48 hours, or within less than or equal to about24 hours under said neutral pH physiological conditions. In someembodiments, the mechanical failure occurs within the linker materialitself, and not at the interface between the linker and the one or morepolymeric components.

Non-limiting examples of suitable linker materials includepolyesters—such as including but not limited to, polycaprolactone,poly(propylene fumarate), poly(glycerol sebacate), poly(lactide),poly(glycol acid), poly(lactic-glycolic acid), polybutyrate, andpolyhydroxyalkanoate; polyethers—such as including but not limited to,poly(ethylene oxide) and poly(propylene oxide); polyamides—such asincluding but not limited to, poly(caprolactam); polyvinyl alcohols;polyoxetanes; polyacrylates/methacrylates—such as including but notlimited to, poly(methyl methacrylate) and poly(ethylene-co-vinylacetate); polyanhydrides; and polyurethanes.

In certain embodiments, the linker comprises an ethyl acrylate, a methylmethacrylate and/or a low content of methacrylic acid ester withquaternary ammonium groups. In some embodiments, the linker comprises awater soluble polymer such as vinylpyrrolidone-vinyl acetate copolymers(e.g., KOLLIDON® VA 64 (BASF) and KOLLIDON® SR), polyvinylpyrrolidone,cellulose acetate, hydroxypropyl methyl cellulose, or polyvinyl alcohol.

In some embodiments, the linker comprises a blend of polymers. In anexemplary embodiment, the linker comprises an isocyanate crosslinkedpolyurethane generated from low-molecular weight polycaprolactonemonomers.

In certain embodiments, the linker comprises an enteric polymer. In someembodiments, the linker comprises an enteric elastomer. Enteric polymersand enteric elastomers are described in more detail, below.

In some embodiments, the linker and/or elastic polymeric componentcomprises an enteric polymer. The term enteric is generally used todescribe materials that are stable at relatively highly acidic pHconditions (e.g., pH of less than about 5.5) and susceptible todissolution at relatively alkaline pH conditions (e.g., pH of betweenabout 6 and about 9). In some embodiments, the enteric polymer includes,but is not limited to, cellulose acetate phthalate (CAP), hypromellose(INN) hydroxypropyl methylcellulose (HPMC), and/or poly(methacrylicacid-co-ethyl acrylate) (e.g., EUDRAGIT® a available from EvonikIndustries AG (Essen, Germany)).

In some embodiments, the dissolution of an enteric polymer can betriggered by, for example, ingestion of an alkali solution. In someembodiments, the enteric polymer has the capacity for dissolutionbetween pH 4-8. According to some embodiments, the enteric polymer isselected such that the enteric polymer is stable in an acidic gastricenvironment (i.e., having a pH1 to pH4) but dissolves in a more alkaliregion of the gastrointestinal tract distal to the pylorus (i.e., havinga pH greater than 5.5) and can serve as a linker.

For example, in certain embodiments, the enteric polymer does notsubstantially degrade at a pH ranging between about 1 and about 5. Insome embodiments, the enteric polymer does not substantially degrade ata pH of at least about 1, at least about 2, at least about 3, at leastabout 4, or at least about 4.5. In certain embodiments, the entericpolymer does not substantially degrade at a pH of less than or equal toabout 5, less than or equal to about 4.5, less than or equal to about 4,less than or equal to about 3, or less than or equal to about 2. Any andall closed ranges that have endpoints within any of the above referenceranges are also possible (e.g., between about 1 and about 4.5, betweenabout 1 and about 5, between about 1 and 4). Other ranges are alsopossible.

In certain embodiments, the enteric polymer degrades substantially at apH ranging between about 4 and about 8. In some embodiments, the entericpolymer degrades substantially at a pH of at least about 4, at leastabout 5, at least about 6, at least about 6.5, at least about 7, or atleast about 7.5. In certain embodiments, the enteric polymer degradessubstantially at a pH of less than or equal to about 8, less than orequal to about 7.5, less than or equal to about 7, less than or equal toabout 6.5, less than or equal to about 6, or less than or equal to about5. Any and all closed ranges that have endpoints within any of the abovereference ranges are also possible (e.g., between about 4 and about 8,between about 5 and about 8, between about 6.5 and about 7.5). Otherranges are also possible.

Those skilled in the art would be capable of selecting suitable methodsfor determining degradation of the enteric polymers based upon theteachings of the specification including, determining the solubility ofthe enteric polymer in an aqueous solution having a pH of less thanabout 3 and/or dissolving the enteric polymer in aqueous solution havinga pH of greater than or equal to about 6, measured at body temperature(e.g., between about 35° C. and about 38° C.) over time period ofbetween about 2 and about 40 days. In some embodiments, the entericpolymer that does not substantially degrade behaves such that less thanabout 10%, less than about 5%, or less than about 2% of the entericpolymer dissociates from the rest of enteric polymer. In certainembodiments, the enteric polymer that substantially degrades behavessuch that at least about 1%, at least about 2%, or at least about 5% ofthe enteric polymer dissociates from the remainder of the polymericcomposite.

According to some embodiments, a structure is configured to maintainsafety with low to no potential for intestinal obstruction and/orperforation. Controlled degradation is important, in some cases, formitigating the risk of gastrointestinal obstruction. In someembodiments, the linker is designed to dissolve distal to the pylorus.In some embodiments, a linker is attached to and/or incorporated into astructure so that upon degradation/dissolution of the linker, thestructure breaks into smaller structures configured for passing througha gastrointestinal tract (e.g., traversing the ileocecal valve) withoutobstruction. In an illustrative embodiment, the linker does notsubstantially dissolve and/or degrade when located in the stomach of asubject (e.g., having a pH ranging between about 1 and about 5) andsubstantially dissolves when located (e.g., after passing through thepylorus) in the intestines (e.g., having a pH ranging between about 6.7and about 7.4).

In some embodiments, the enteric polymer is an enteric elastomer. Forexample, in some embodiments, the linker comprises a material selectedsuch that it has both enteric and elastic properties. For example, insome embodiments, the linker comprises an enteric elastomer that has anelastic modulus between about 0.1 MPa and about 100 MPa at relativelyhighly acidic pH conditions (e.g., pH of less than about 5.5) and issusceptible to dissolution at relatively alkaline pH conditions.

In certain embodiments, at least one dimension of the enteric elastomerexhibits reversible elongation when the dimension is deformed from itsinitial length to a length that is less than about 50% of its originallength and/or when the dimension is deformed from its initial length toa length that is at least about 1500% of its initial length. That is tosay, in some embodiments, the enteric elastomer has difference inaverage length after deformation versus before deformation (e.g.,stretching) of less than about 10%, less than about 5%, less than about2%, or less than about 1%. For example, in some embodiments, the entericelastomer is capable of exhibiting reversible elongation when stretchedfrom at least about 50%, at least about 100%, at least about 200%, atleast about 400%, at least about 500%, at least about 1000%, at leastabout 1200%, or at least about 1400% of its initial length. In certainembodiment, the enteric elastomer is capable of exhibiting reversibleelongation when stretched from less than or equal to about 1500%, lessthan or equal to about 1400%, less than or equal to about 1200%, lessthan or equal to about 1000%, less than or equal to about 500%, lessthan or equal to about 400%, less than or equal to about 200%, or lessthan or equal to about 100% of its initial length. Any and all closedranges that have endpoints within any of the above referenced ranges arealso possible (e.g., between about 50% and about 1500%, between abouthundred percent and about 1500%, between about 200% and about 1000%,between about 500% and about 1400%). Other ranges are also possible.

In certain embodiments, the enteric elastomer has an elastic modulusranging between about 0.1 MPa and about 100 MPa. In some embodiments,the elastic modulus of the enteric elastomer is at least about 0.1 MPa,at least about 0.2 MPa, at least about 0.3 MPa, at least about 0.5 MPa,at least about 1 MPa, at least about 2 MPa, at least about 5 MPa, atleast about 10 MPa, at least about 25 MPa, or at least about 50 MPa. Incertain embodiments, the elastic modulus of the enteric elastomer isless than or equal to about 100 MPa, less than or equal to about 50 MPa,less than or equal to about 25 MPa, less than or equal to about 10 MPa,less than or equal to about 5 MPa, less than or equal to about 2 MPa,less than or equal to about 1 MPa, less than or equal to about 0.5 MPa,less than or equal to about 0.3 MPa, or less than or equal to about 0.2MPa. Any and all closed ranges that have endpoints within any of theabove referenced ranges are also possible (e.g., between about 0.1 MPaand about 100 MPa, between about 0.3 MPa and about 10 MPa). Other rangesare also possible. Those skilled in the art would be capable ofselecting suitable methods for determining the elastic modulus of anenteric elastomer including, for example, tensile mechanicalcharacterization under ASTM D638 and/or compressive mechanicalcharacterization under ASTM D575.

In certain embodiments, the enteric elastomer comprises a polymericmixture of varying ratios of poly(acryloyl-6-aminocaproic acid) andpoly(methacrylic acid-co-ethyl acrylate).

In some embodiments, the enteric elastomer comprises a polymer of aacryloylaminoalkylene acid monomer, or salts thereof. In someembodiments, the enteric elastomer comprises a polymer of anacryloylaminoalkylene acid monomer, a (meth)acryloylaminoalkylene acidmonomer, or salts thereof. In certain embodiments, theacryloylaminoalkylene acid monomer is selected from the group consistingof acryloyl-5-aminopentanoic acid, acryloyl-6-aminocaproic acid,acryloyl-7-aminoheptanoic acid, acryloyl-8-aminooctanoic acid,acryloyl-9-aminononanoic acid, acryloyl-10-aminodecanoic acid,acryloyl-11-aminoundecanoic acid, acryloyl-12-aminododecanoic acid,methacryloyl-5-aminopentanoic acid, methacryloyl-6-aminocaproic acid,methacryloyl-7-aminoheptanoic acid, methacryloyl-8-aminooctanoic acid,methacryloyl-9-aminononanoic acid, methacryloyl-10-aminodecanoic acid,methacryloyl-11-aminoundecanoic acid, methacryloyl-12-aminododecanoicacid, salts thereof, and combinations thereof.

In certain embodiments, the enteric elastomer comprises a homopolymer ofacryloyl-6-aminocaproic acid or salts thereof. In some embodiments, theenteric elastomer comprises a copolymer of acryloyl-6-aminocaproic acidor salts thereof. In certain embodiments, enteric elastomer comprisespoly(methacrylic acid-co-ethyl acrylate) or salts thereof. In somecases, the poly(methacrylic acid-co-ethyl acrylate) has a molar ratio ofmethacrylic acid monomer units to ethylacrylate monomer units of about1:1.

In some embodiments, the enteric elastomer is a blend. For example, incertain embodiments, the enteric elastomer comprises a first entericpolymer (e.g., poly(acryloyl-6-aminocaproic acid)) and a second entericpolymer (e.g., poly(methacrylic acid-co-ethyl acrylate)). In some suchembodiments, the weight ratio of the first polymer to the second polymerranges from about 1:6 to about 6:1. In certain embodiments, the weightratio of the first polymer to the second polymer is at least about 1:6,at least about 1:5, at least about 1:4, at least about 1:3, at leastabout 1:2, at least about 1:1, at least about 2:1, at least about 3:1,at least about 4:1, or at least about 5:1. In some embodiments, theweight ratio of the first polymer to the second polymer is less than orequal to about 6:1, less than or equal to about 5:1, less than or equalto about 4:1, 3:1, less than or equal to about 2:1, less than or equalto about 1:1, less than or equal to about 1:2, less than or equal toabout 1:3, less than or equal to about 1:4, or less than or equal toabout 1:5. Combinations of the above referenced ranges are also possible(e.g., between about 1:6 and about 6:1, between about 1:4 and about 4:1,between about 1:3 and about 3:1, between about 1:2 and about 2:1,between about 1:3 and about 1:1, between about 1:1 and about 3:1). Otherranges are also possible.

In some embodiments, the enteric elastomer is a polymer gel with watercontent no greater than 40%. For example, in some embodiments, theenteric elastomer has a water content of less than or equal to about 40wt %, less than or equal to about 30 wt %, less than or equal to about20 wt %, or less than or equal to about 10 wt %. In some embodiments,the enteric elastomer has a water content greater than about 5 wt %,greater than about 10 wt %, greater than about 20 wt %, or greater thanabout 30 wt %. Combinations of the above-referenced ranges are alsopossible (e.g., between about 5 wt % and about 40 wt %).

The enteric elastomer can be used as a material platform. In someembodiments, this material platform features tunable elastomericproperties, is stable in an acidic environment, and/or dissolvable in amore alkali environment. Thus, the enteric elastomer material platformis compatible with the acidic gastric environment and has the capacityfor targeted dissolution in the small intestinal/colonic environment.According to some embodiments, the enteric elastomer material platformis useful for many applications, including, but not limited to,gastrointestinal structure manufacturing, and gastrointestinal-specificdrug delivery with targeted release beyond the pylorus.

For example, one or more enteric elastomer linkers attached to and/orincorporated into a structure in a gastric cavity can mitigate the riskof accidental passage of the macrostructure, which could induceobstruction and/or penetration, because the rapid dissolution of the oneor more linkers upon passage through the pylorus would reduce themacrostructure to smaller, previously-linked portions.

A structure bonded with an enteric elastomer can be subject todissolution in the presence of an alkali environment. Thus, in the caseof a gastric structure resident in vivo and comprising an entericelastomer, passage of the structure can be induced if the subjectingests an alkali solution (e.g., sodium bicarbonate) to induce thedissolution of the enteric elastomer to enable breakdown of thestructure in accordance with some embodiments.

In some embodiments, the enteric elastomer linker has substantialflexibility. Flexibility can enable packing and/or folding of astructure to, for example, fit into a confined/predefined vessel such ascapsule for oral administration or a catheter for endoscopic deployment,as described herein. In some embodiments, the enteric elastomer hasflexibility to 180 degrees to enable tight and/or maximal packing and/orfolding (e.g., for use as an elastic polymeric component, as describedabove).

In some embodiments, the structure (e.g., comprising one or morepolymeric components) comprises one or more configurations. For example,in certain embodiments, the structure has a particular configurationsuch as a defined shape, size, orientation, and/or volume. The structuremay comprise any suitable configuration. In some embodiments, thestructure has a particular shape as defined by a cross-sectional area ofthe structure. Non-limiting examples of suitable cross-sectional shapesinclude square, circles, ovals, polygons (e.g., pentagons, hexagons,heptagons, octagons, nonagons, dodecagons, or the like), tubes, rings,star or star-like/stellate (e.g, 3-armed stars, 4-armed stars, 5-armedstars, 6-armed stars, 7-armed stars, 8-armed stars), or the like. Thoseskilled in the art would be capable of selecting suitable shapesdepending on the application (e.g., a stellate shape for gastricretention structures) and based upon the teachings of thisspecification.

The structure may, in some cases, have an original configuration whichmay be modified (e.g., deformed) such that the structure obtains a newconfiguration, different than the original configuration. For example,in some embodiments, the structure has a first configuration and asecond configuration, different than the first configuration, e.g., whencompressed.

In certain embodiments, the configuration of the structure may becharacterized by a largest cross-sectional dimension. In someembodiments, the largest cross-sectional dimension of the firstconfiguration may be at least about 10% less, at least about 20% less,at least about 40% less, at least about 60% less, or at least about 80%less than the largest cross-sectional dimension of the secondconfiguration. In certain embodiments, the largest cross-sectionaldimension of the second configuration may be at least about 10% less, atleast about 20% less, at least about 40% less, at least about 60% less,or at least about 80% less than the largest cross-sectional dimension ofthe first configuration. Any and all closed ranges that have endpointswithin any of the above referenced ranges are also possible (e.g.,between about 10% and about 80%, between about 10% and about 40%,between about 20% and about 60%, between about 40% and about 80%). Otherranges are also possible.

In some embodiments, the configuration of the structure may becharacterized by a convex hull volume of the structure. The term convexhull volume is known in the art and generally refers to a set ofsurfaces defined by the periphery of a 3-D object such that the surfacesdefine a particular volume. For example, as illustrated in FIG. 1D, a 3Dstar-like object 150 has a convex hull volume as defined by convex hull160. In some embodiments, the convex hull volume of the firstconfiguration may be at least about 10% less, at least about 20% less,at least about 40% less, at least about 60% less, or at least about 80%less than the convex hull volume of the second configuration. In certainembodiments, the convex hull volume of the second configuration may beat least about 10% less, at least about 20% less, at least about 40%less, at least about 60% less, or at least about 80% less than theconvex hull volume of the first configuration. Any and all closed rangesthat have endpoints within any of the above referenced ranges are alsopossible (e.g., between about 10% and about 80%, between about 10% andabout 40%, between about 20% and about 60%, between about 40% and about80%). Other ranges are also possible.

Those skilled in the art would understand that the differences betweenthe first configuration and the second configuration do not refer to aswelling or a shrinking of the structure (e.g., in the presence of asolvent), but instead refers to a change in shape and/or orientation ofat least a portion of the structure (e.g., in the presence of a stimulussuch as heat and/or mechanical pressure/compression), although somedegree of swelling or shrinking may occur between the twoconfigurations.

In some embodiments, the first configuration is constructed and arrangedsuch that a structure is retained at a location internal of a subject,and the second configuration is constructed and arranged such that thestructure may be encapsulated (e.g., for oral delivery of the structurewithin a capsule). In some cases, the first configuration issufficiently large such that the structure is retained at a locationinternal of the subject and the second configuration is sufficientlysmall such that the structure may fit within a particular size capsulesuitable for oral delivery to a subject.

In certain embodiments, the structure may be polymerized and/or cast ina first configuration, mechanically deformed such that the structureobtains a second configuration, and placed in a capsule or restrained bysome other containment structure. The structure may be mechanicallydeformed using any suitable method including, for example, bending,twisting, folding, molding (e.g., pressing the material into a moldhaving a new shape), expanding (e.g., applying a tensile force to thematerial), compressing, and/or wrinkling the structure. The structuremay maintain the second configuration for any suitable duration prior tostimulation/release. Advantageously, certain embodiments of thestructures described herein may be relatively stable in the first and/orsecond configurations such that the structure may be stored for longperiods of time without significant degradation of mechanical propertiesof the one or more components and/or one or more linkers. In someembodiments, the structure may be stable under ambient conditions (e.g.,room temperature, atmospheric pressure and relative humidity) and/orphysiological conditions (e.g., at or about 37° C., in physiologicfluids) for at least about 1 day, at least about 3 days, at least about7 days, at least about 2 weeks, at least about 1 month, at least about 2months, at least about 6 months, at least about 1 year, or at leastabout 2 years. In certain embodiments, the structure has a shelf life ofless than or equal to about 3 years, less than or equal to about 2years, less than or equal to about 1 year, less than or equal to about 1month, less than or equal to about 1 week, or less than or equal toabout 3 days. Any and all closed ranges that have endpoints within anyof the above-referenced ranged are also possible (e.g., between about 24hours and about 3 years, between about 1 week and 1 year, between about1 year and 3 years). Other ranges are also possible.

In some embodiments, the structure in the second configuration mayrecoil such that the structure reverts to the first configuration. Forexample, in some embodiments, the structure in the second configurationis contained within a capsule and delivered orally to a subject. In somesuch embodiments, the structure may travel to the stomach and thecapsule may release the structure from the capsule, upon which thestructure obtains (e.g., recoils to) the first configuration.

As described herein, in some embodiments, the structure may comprise oneor more linkers and/or one or more components with particular mechanicalproperties (e.g., elastic polymeric components) such that the structurewill substantially recoil after being mechanically deformed. Thestructure may be characterized, in some cases, by a folding force. Theterm folding force generally refers to the force required to compressthe structure into a cavity having a cross-sectional area of less thanabout 2 cm (e.g., such as the pylorus). In some embodiments, the foldingforce of the structure is at least about 0.2 N, at least about 0.5 N, atleast about 0.7 N, at least about 1 N, at least about 1.5 N, at leastabout 2 N, at least about 2.5 N, or at least about 3 N. In certainembodiments, the folding force of the structure is less than or equal toabout 5 N, less than or equal to about 3 N, less than or equal to about2.5 N, less than or equal to about 2 N, less than or equal to about 1.5N, less than or equal to about 1 N, less than or equal to about 0.7 N,or less than or equal to about 0.5 N. Any and all closed ranges thathave endpoints within any of the above-referenced ranges are alsopossible (e.g., between about 0.2 N and about 3 N, between about 0.2 Nand about 2.5 N, between about 0.5 N and about 1.5N, between about 1 Nand about 3 N). Other ranges are also possible. The folding force may bedetermined by, for example, by placing the structure in a funnel (shownin FIG. 13A) having a 20 cm upper diameter and a 2 cm lower diameter(e.g., simulating the pyloric sphincter) and measuring the forcesrequired to move the structure through the 2 cm lower diameter. Aplunger may be attached to the tension cross-head of an tensile loadingmachine and the funnel to a clamp, and the structure pushed through thefunnel at a rate of, for example, 10 mm/min, which measuring the forceand displacement. The folding force is generally determined by measuringthe force at which the structure folds and enters the 2 cm lowerdiameter tube.

In certain embodiments, the structure in the first configuration has anuncompressed cross-sectional dimension. The uncompressed cross-sectionaldimension is generally selected such that the structure is retained at alocation internally to a subject for a relatively long period of time(e.g., at least about 24 hours) even under physiological compressiveforces (e.g., such as those in the digestive tract).

In some embodiments, the uncompressed cross-sectional dimension of thefirst configuration is at least about 2 cm, at least about 4 cm, atleast about 5 cm, or at least about 10 cm. In certain embodiments, theuncompressed cross-sectional dimension of the first configuration isless than or equal to about 15 cm, less than or equal to about 10 cm,less than or equal to about 5 cm, or less than or equal to about 4 cm.Any and all closed ranges that have endpoints within any of theabove-referenced ranges are also possible (e.g., between about 2 cm andabout 15 cm). Those skilled in the art would be capable of selectingsuitable uncompressed cross-sectional dimensions for structures basedupon the teachings of this specification for specific orifices of asubject such that the structure is retained.

As described herein, in some embodiments, the one or more polymericcomponents of the structure may be cast, molded, and/or cut to have aparticular shape, size, and/or volume. For example, in an exemplaryembodiment, one or more elastic polymeric components, one or moreloadable polymeric components, and/or one or more linkers arepolymerized independently into sheets and cut into desired shapes and/orsizes. The cut components and linkers may then be assembled (e.g., in amold) and treated such that the one or more components and linkers arecoupled. In certain embodiments, one or more elastic polymericcomponents, one or more loadable polymeric components, and/or one ormore linkers are polymerized independently in molds of desired shapes.In some embodiments, the one or more components and/or linkers areadhered via an adhesive. In certain embodiments, the one or morecomponents and/or linkers are heated such that the one or morecomponents and/or linkers are coupled (e.g., via bonding and/orentanglement), as described herein.

In an exemplary embodiment, a shape configured for residence such asgastric residence comprises a three-dimensional elliptical ringstructure (i.e., an elliptical outline when projected onto a flatsurface). In some embodiments, the elliptical ring structure has a minoraxis diameter comparable to the major axis of a capsule. In someembodiments, the elliptical ring structure comprises a loadablepolymeric component and one or more linkers configured to degrade in acontrolled manner attached to and/or incorporated into the ellipticalring structure. In some embodiments, one or more linkers areincorporated into the elliptical ring structure at one or more pointsalong the minor axis. In further embodiments, one or more controlleddegradation linkers are incorporated into the elliptical ring structureat one or more points along the major axis. According to someembodiments, the elliptical ring structure may be twisted into a formsimilar to a double helix for packing into a soluble container and/orbinding with a retention element. In some embodiments, the ellipticalring structure is twisted such that the axis of the helix is along theminor axis of the elliptical ring structure to avoid bending the helixto pack it into a soluble container.

In some embodiments, a shape configured for residence (e.g., beingretained in an orifice at a particular location internal to a subject)such as gastric residence comprises a three-dimensional structure havinga plurality of projections (i.e. arms). In some embodiments, thestructure with projections comprises a flexible material configured forelastic (non-plastic) deformation. The projections themselves may beflexible or rigid with flexible connections to a core. In someembodiments, one or more controlled degradation linkers (e.g., entericelastomers) are attached to and/or incorporated into the structure, forexample, along one or more projections, such as near or at theconnection to a core. In some embodiments, each projection has a lengthequal to just less than the length of a soluble container such that theunencapsulated final form has a diameter equal to nearly twice thesoluble container length. In some embodiments, the projections each mayhave a length of about 0.5 cm to about 2.5 cm (e.g., such that thestructure has an uncompressed cross-sectional dimension of at leastabout 2 cm).

In certain embodiments, the projections are arranged based onbio-inspired flower bud designs in which a number (N) of radial spokesor petals project from a central linking core. In some embodiments,these radial projections each have an internal sector angle ofapproximately 360°/N, where N is the total number of radial projections.In some cases, this enhances the packing volume of the encapsulatedstructure, thus increasing drug carrying capacity. In some embodiments,the projections are formed of a material with a relatively high elasticmodulus to increase the resistance to compression and duration ofgastric residence, as described herein.

In some embodiments, the one or more linkers are attached to and/orincorporated into the structure. For example, as illustrated in FIG. 1E,structure 102 comprises a first configuration comprising a 6-armedstar-like shape. While a 6-armed star-like shape is shown here, thoseskilled in the art would understand that FIG. 1E is meant to benon-limiting and that the structure could have 3, 4, 5, 6, 7, 8, 9, 10,or more arms, as described herein, and each could vary in length, numberof components, and/or linkers.

Structure 102 comprises elastic polymeric component 110 coupled withloadable polymeric components 120. For example, loadable polymericcomponent 120 may be coupled with elastic polymeric component 110 viaoptional first linkers 130. In certain embodiments, elastic polymericcomponent 110 comprises an enteric elastomer. Additional loadablepolymeric components 120 may be coupled together via optional secondlinker 135, different than optional linker 130. The number and/orlocation of linkers may be chosen as part of certain design parameters(e.g., such that the structure has certain degradation properties and/orconfigurations). The location of the linkers may also vary. For example,as shown by optional linker 134 (dashed), the linkers may be embeddedwithin one or more loadable polymeric components 120.

Structure 102 may be folded into a second configuration, as illustratedin FIG. 1F, such that the structure may be encapsulated. Those skilledin the art would understand that FIG. 1F is meant to be non-limiting,and the structure shown in FIG. 1E could be folded into additionalconfigurations.

According to some embodiments, a shape configured for residence (e.g.,being retained in an orifice at a particular location internal to asubject) such as a gastric residence comprises a three-dimensionalstructure forming a polygon outline with, for example, 3, 4, 6, 8, 10,12, 14, 16, 18, or 20 sides, when projected onto a flat surface. In someembodiments, each side has a length equal to just less than the lengthof a soluble container. In some embodiments, the structure comprises aflexible material configured for elastic (non-plastic) deformation suchthat the structure is configured for bending at its vertices and packinginto a soluble container. Materials with low elastic moduli, with lowcreep deformation and/or good recoil, and configured for large elasticdeformation may be used at the vertices to facilitate stable packing. Insome embodiments, individual sides each have an internal sector angle ofapproximately 360°/N, where N is the total number of sides, to obtainmaximal packing.

In some embodiments, one or more linkers are attached to and/orincorporated into the structure. In certain embodiments, a flexiblelinker configured for high degree of elastic deformation and controlleddegradation (e.g., comprising an enteric elastomer) is located at eachof the vertices between the sides of the polygon.

For example, as illustrated in FIG. 1G, structure 104 comprises a firstconfiguration comprising a hexagon. While a hexagonal shape is shownhere, those skilled in the art would understand that FIG. 1G is meant tobe non-limiting and that the structure could have 4, 6, 8, 10, 12, ormore sides, as described herein, and each could vary in length, numberof components, and/or linkers.

Structure 104 comprises elastic polymeric component 110 coupled withloadable polymeric components 120. For example, elastic polymericcomponent 110 and loadable polymeric component 120 may be coupled withelastic polymeric component 110 via optional linkers 130 or 135,different than optional linker 130. In some embodiments, elasticpolymeric component 110 comprises an enteric elastomer. The numberand/or location of linkers may be chosen as part of certain designparameters (e.g., such that the structure has certain degradationproperties and/or configurations). The location of the linkers may alsovary. For example, as shown by optional linker 134 (dashed), the linkersmay be embedded within one or more loadable polymeric components 120.

Structure 104 may be folded into a second configuration, as illustratedin FIG. 1H, for encapsulation. Those skilled in the art would understandthat FIG. 1H is meant to be non-limiting, and the structure shown inFIG. 1G could be folded into additional configurations.

In an exemplary embodiment, the linkers coupling the elastic polymericcomponent and the loadable polymeric component (optional linker 130) maybe time-dependent degradable linkers (e.g., such that the arms of thestructure detach after a particular length of time). In certainembodiments, the linkers coupling and/or embedded within the loadablepolymer components together (optional linkers 135 and 134) may compriseenteric polymers, such that the loadable polymer components decouplewhen exposed to pH greater than about 5. For example, the structuresillustrated in FIGS. 1E-1H may be delivered (e.g., orally administered)to a subject via a capsule (containing the structure in the secondconfiguration) and released (obtaining the first configuration), andretained, at a location internal to the subject such as the stomachbefore the pylorus. After a particular length of time (e.g., theresidence time period such as at least about 24 hours), thetime-dependent degradable linker may degrade and the structure separatesinto several units, which pass through the pylorus. Upon entry into theintestines (e.g., at pH greater than about 5), the linkers comprising anenteric polymer degrade and the arms further separate into smaller, moreeasily removed, units.

In some cases, the active substance may be loaded into beads and/orparticles comprising the loadable polymeric material embedded within anelastic polymer such as an elastic degradable linker (e.g., comprisingan enteric elastomer). In some embodiments, the loadable polymericcomponent comprises beads and/or particles dispersed/embedded within oneor more elastic polymer components and/or one or more linkers. Forexample, in certain embodiments, the loadable polymeric componentbeads/particles may be coupled with the elastic polymer component and/oradditional loadable polymeric component beads/particles via a linker(e.g., where the linker is physically attached the loadable polymericcomponent or at least partially encapsulates the loadable polymericcomponent).

Various packing/folding strategies can be used to minimize the size of astructure for encapsulation and/or maximize the size of a structure forgastric residence in accordance with some embodiments. In someembodiments, a polygonal structure with a triangular cross-section formsa triangle when projected onto a plane as shown in FIG. 2. According tothis embodiment, each side of the three sides of the triangle isconfigured to fold in half at a hinge which results in high packingdensity with six total sides once folded.

Typical residence structures known in the art such as intragastricballoons generally result in at least partial gastric outlet obstructionin subjects. Advantageously, in some embodiments, the structurecomprises a shape with sufficient void space (or fenestrations) to allowthe passage of food material including indigestible substances therebyavoiding partial or complete gastric outlet obstruction, when located inor at an orifice internally of the subject.

In some embodiments, the structure is fenestrated. In an exemplaryembodiment, referring again to FIG. 1G, the structure has a polygonalcross-sectional area defined by an external surface of the structure. Insome such embodiments, the structure comprising one or more polymericcomponents and linkers has an internal cross-sectional area thatcomprises one or more voids (i.e. does not comprise one or morepolymeric components and linkers), such that food and other substancesmay pass through the structure.

In another exemplary embodiment, referring again to FIG. 1E, thestructure has a star-like configuration such that food and othersubstances may pass between the arms of the structure (e.g., whenresident in a location internally of a subject).

As described above, in some embodiments, the initial (undeformed)configuration of the structure may be characterized by a convex hullvolume. In some embodiments, the structure comprising one or morepolymeric components and linkers (i.e. the solid components of thestructure as opposed to void space) occupies between about 10 vol % andabout 90 vol % of the total convex hull volume of the initialconfiguration. For example, in certain embodiments, the structureoccupies less than or equal to about 90 vol %, less than or equal toabout 80 vol %, less than or equal to about 70 vol %, less than or equalto about 60 vol %, less than or equal to about 50 vol %, less than orequal to about 40 vol %, less than or equal to about 30 vol %, or lessthan or equal to about 20 vol % of the convex hull volume of the initialconfiguration. In some embodiments, the structure occupies at leastabout 10 vol %, at least about 20 vol %, at least about 30 vol %, atleast about 40 vol %, at least about 50 vol %, at least about 60 vol %,at least about 70 vol %, or at least about 80 vol % of the convex hullvolume of the initial configuration. Any and all closed ranges that haveendpoints within any of the above referenced ranges are also possible(e.g., between about 10 vol % and about 90 vol %, between about 30 vol %and about 90 vol %, between about 20 vol % and about 50 vol %, betweenabout 40 vol % and about 60 vol %, between about 40 vol % and about 90vol %). Other ranges are also possible.

As described herein, in some embodiments, the structure is configured toadopt a shape and/or size compatible with oral administration to and/oringestion by a subject. In some embodiments, the structure has a shapewith a capacity for folding and/or packing into stable encapsulatedforms. For example, in some embodiments the structure is designed tomaximally pack and fill a capsule or other soluble container (e.g., acontaining structure). In some embodiments, the structure has a shapethat maximally fills and/or packs into a capsule or other solublecontainer.

In some embodiments, the system comprises the structure and a containingstructure. In some embodiments, the structure comprises more than 60 vol% of the containing structure. Based on the application, a capsule maybe manufactured to particular specifications or a standard size,including, but not limited to, a 000, 00, 0, 1, 2, 3, 4, and 5, as wellas larger veterinary capsules Su07, 7, 10, 12e1, 11, 12, 13, 110 ml, 90ml, and 36 ml. In some embodiments, the structure may be provided incapsules, coated or not. The capsule material may be either hard orsoft, and as will be appreciated by those skilled in the art, typicallycomprises a tasteless, easily administered and water soluble compoundsuch as gelatin, starch or a cellulosic material.

In other embodiments, the structure is retained in a packed shape by asoluble retaining element, such as a band or surgical thread. In someembodiments, the structure comprises optimal combinations of materialswith high and low elastic moduli, giving the structure the capacity toalter its shape and/or size once the soluble container and/or solubleretaining element is removed.

For example, consider a human patient with hypothyroidism, who isprescribed levothyroxine with the dosing level held stable at 125 μg perday for six months (e.g., between checks of thyroid-stimulatinghormone). During those six months, the patient should undergo 168 drugadministration events, each event involving an administration dose of125 μg. According to some embodiments, a structure configured forcontrollable gastric residence is loaded with in excess of 21 mg oflevothyroxine (i.e., 125 μg per day for 168 days), and configured torelease about 125 μg per day. Thus, the patient undergoes one drugadministration versus 168 drug administration events over the same timeperiod with comparable efficacy.

Similarly, consider a human patient infected with hepatitis B, treatedwith daily doses of entecavir. According to some embodiments, astructure configured for controllable gastric residence is loaded withabout 84 mg of entecavir (i.e., 0.5 mg per day for 168 days) so that thepatient undergoes one drug administration versus 168 drug administrationevents over the same time period with the same results. In another case,consider a human patient with at least one of Barrett's esophagus, agastric ulcer, and gastroesophageal reflux disease, treated withomeprazole. According to some embodiments, a structure configured forcontrollable gastric residence is loaded with about 3,360 mg ofomeprazole (i.e., 20 mg per day for 168 days) so that the patientundergoes one drug administration versus 168 drug administration eventsover the same time period with comparable efficacy.

In another example, consider a human patient with an exacerbation orflare of at least one of chronic obstructive pulmonary disease,ulcerative colitis, asthma, and gout. The patient, is prescribedprednisone with an initial daily dosing level held stable for two weeksthen tapered off over an additional number of days, for example, 23 ormore total days of prednisone treatment. During treatment, the patientshould undergo 23 drug administration events, each event involving oneof at least two predetermined administration doses. According to someembodiments, a structure configured for controllable gastric residenceis loaded with about 770 mg of prednisone and configured to release afirst predetermined administration dose each day for two weeks followedby lower predetermined administration doses on the days after. Thus, thepatient undergoes one drug administration versus 23 or more drugadministration events over the same time period with the same results.Further, the patient will not have to be vigilant as to the dosechange(s) because the structure is preconfigured to automatically taperthe dosage.

In another case, consider a human patient with coronary artery diseaseundergoing dual antiplatelet therapy. The patient, is prescribed eitherclopidogrel or prasugrel with a daily dosing level held stable for atleast three months. During treatment, the patient should undergo about90 drug administration events. According to some embodiments, astructure configured for controllable gastric residence is loaded withabout 6,750 mg of clopidogrel (i.e., 75 mg per day for 90 days) or 900mg of prasugrel (i.e., 10 mg per day for 90 days) so that the patientundergoes one drug administration versus 90 drug administration eventsover the same time period with comparable efficacy. In another example,consider a human patient with at least one of hyperlipidemia andcoronary artery disease, treated with rosuvastatin. According to someembodiments, a structure configured for controllable gastric residenceis loaded with about 1,800 mg of rosuvastatin (i.e., 10 mg per day for180 days) so that the patient undergoes one drug administration versus180 drug administration events over the same time period with comparableefficacy.

Any terms as used herein related to shape, orientation, alignment,and/or geometric relationship of or between, for example, one or morearticles, compositions, structures, materials and/or subcomponentsthereof and/or combinations thereof and/or any other tangible orintangible elements not listed above amenable to characterization bysuch terms, unless otherwise defined or indicated, shall be understoodto not require absolute conformance to a mathematical definition of suchterm, but, rather, shall be understood to indicate conformance to themathematical definition of such term to the extent possible for thesubject matter so characterized as would be understood by one skilled inthe art most closely related to such subject matter. Examples of suchterms related to shape, orientation, and/or geometric relationshipinclude, but are not limited to terms descriptive of: shape—such as,round, square, circular/circle, rectangular/rectangle,triangular/triangle, cylindrical/cylinder, elipitical/elipse,(n)polygonal/(n)polygon, etc.; angular orientation—such asperpendicular, orthogonal, parallel, vertical, horizontal, collinear,etc.; contour and/or trajectory—such as, plane/planar, coplanar,hemispherical, semi-hemispherical, line/linear, hyperbolic, parabolic,flat, curved, straight, arcuate, sinusoidal, tangent/tangential, etc.;surface and/or bulk material properties and/or spatial/temporalresolution and/or distribution—such as, smooth, reflective, transparent,clear, opaque, rigid, impermeable, uniform(ly), inert, non-wettable,insoluble, steady, invariant, constant, homogeneous, etc.; as well asmany others that would be apparent to those skilled in the relevantarts. As one example, a fabricated article that would described hereinas being “square” would not require such article to have faces or sidesthat are perfectly planar or linear and that intersect at angles ofexactly 90 degrees (indeed, such an article can only exist as amathematical abstraction), but rather, the shape of such article shouldbe interpreted as approximating a “square,” as defined mathematically,to an extent typically achievable and achieved for the recitedfabrication technique as would be understood by those skilled in the artor as specifically described.

The term “subject,” as used herein, refers to an individual organismsuch as a human or an animal. In some embodiments, the subject is amammal (e.g., a human, a non-human primate, or a non-human mammal), avertebrate, a laboratory animal, a domesticated animal, an agriculturalanimal, or a companion animal. In some embodiments, the subject is ahuman. In some embodiments, the subject is a rodent, a mouse, a rat, ahamster, a rabbit, a dog, a cat, a cow, a goat, a sheep, or a pig.

The term “electrophile,” as used herein, refers to a functionality whichis attracted to an electron and which participates in a chemicalreaction by accepting an electron pair in order to bond to anucleophile.

The term “nucleophile” as used herein, refers to a functionality whichdonates an electron pair to an electrophile in order to bond to aelectrophile.

As used herein, the term “react” or “reacting” refers to the formationof a bond between two or more components to produce a stable, isolablecompound. For example, a first component and a second component mayreact to form one reaction product comprising the first component andthe second component joined by a covalent bond. The term “reacting” mayalso include the use of solvents, catalysts, bases, ligands, or othermaterials which may serve to promote the occurrence of the reactionbetween component(s). A “stable, isolable compound” refers to isolatedreaction products and does not refer to unstable intermediates ortransition states.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. The alkyl groups may be optionallysubstituted, as described more fully below. In one embodiment, the alkylgroup is a C1-C8 alkyl. Examples of alkyl groups include, but are notlimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, 2-ethylhexyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. “Heteroalkyl” groups are alkyl groups whereinat least one atom is a heteroatom (e.g., oxygen, sulfur, nitrogen,phosphorus, etc.), with the remainder of the atoms being carbon atoms.Examples of heteroalkyl groups include, but are not limited to, alkoxy,poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl,piperidinyl, morpholinyl, etc.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous to the alkyl groups described above, but containing at leastone double or triple bond respectively. In one embodiment, the alkenylgroup is a C2-C8 alkenyl group and in one embodiment the alkynyl groupis a C2-C8 alkynyl group. The “heteroalkenyl” and “heteroalkynyl” referto alkenyl and alkynyl groups as described herein in which one or moreatoms is a heteroatom (e.g., oxygen, nitrogen, sulfur, and the like).

The term “aryl” refers to an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple fusedrings in which at least one is aromatic (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), alloptionally substituted. In one embodiment, the aryl group is a C6-C10aryl group. “Heteroaryl” groups are aryl groups wherein at least onering atom in the aromatic ring is a heteroatom, with the remainder ofthe ring atoms being carbon atoms. Examples of heteroaryl groups includefuranyl, thienyl, pyridyl, pyrrolyl, N lower alkyl pyrrolyl, pyridyl Noxide, pyrimidyl, pyrazinyl, imidazolyl, indolyl and the like, alloptionally substituted.

The terms “amine” and “amino” refer to both unsubstituted andsubstituted amines, e.g., a moiety that can be represented by thegeneral formula: N(R′)(R″)(R′″) wherein R′, R″, and R′″ eachindependently represent a group permitted by the rules of valence.

The terms “acyl,” “carboxyl group,” or “carbonyl group” are recognizedin the art and can include such moieties as can be represented by thegeneral formula:

wherein W is H, OH, O-alkyl, O-alkenyl, or a salt thereof. Where W isO-alkyl, the formula represents an “ester.” Where W is OH, the formularepresents a “carboxylic acid.” In general, where the oxygen atom of theabove formula is replaced by sulfur, the formula represents a“thiolcarbonyl” group. Where W is a S-alkyl, the formula represents a“thiolester.” Where W is SH, the formula represents a “thiolcarboxylicacid.” On the other hand, where W is alkyl, the above formula representsa “ketone” group. Where W is hydrogen, the above formula represents an“aldehyde” group.

As used herein, the term “heteroaromatic” or “heteroaryl” means amonocyclic or polycyclic heteroaromatic ring (or radical thereof)comprising carbon atom ring members and one or more heteroatom ringmembers (such as, for example, oxygen, sulfur or nitrogen). Typically,the heteroaromatic ring has from 5 to about 14 ring members in which atleast 1 ring member is a heteroatom selected from oxygen, sulfur, andnitrogen. In another embodiment, the heteroaromatic ring is a 5 or 6membered ring and may contain from 1 to about 4 heteroatoms. In anotherembodiment, the heteroaromatic ring system has a 7 to 14 ring membersand may contain from 1 to about 7 heteroatoms. Representativeheteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl,imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl,thiadiazolyl, pyrazinyl, quinolyl, isoquinolyl, indazolyl, benzoxazolyl,benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl,tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, benzoxadiazolyl, carbazolyl, indolyl,tetrahydroindolyl, azaindolyl, imidazopyridyl, qunizaolinyl, purinyl,pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl, benzo(b)thienyl, and thelike. These heteroaryl groups may be optionally substituted with one ormore substituents.

The term “substituted” is contemplated to include all permissiblesubstituents of organic compounds, “permissible” being in the context ofthe chemical rules of valence known to those of ordinary skill in theart. In some cases, “substituted” may generally refer to replacement ofa hydrogen with a substituent as described herein. However,“substituted,” as used herein, does not encompass replacement and/oralteration of a key functional group by which a molecule is identified,e.g., such that the “substituted” functional group becomes, throughsubstitution, a different functional group. For example, a “substitutedphenyl” must still comprise the phenyl moiety and cannot be modified bysubstitution, in this definition, to become, e.g., a heteroaryl groupsuch as pyridine. In a broad aspect, the permissible substituentsinclude acyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic substituents of organiccompounds. Illustrative substituents include, for example, thosedescribed herein. The permissible substituents can be one or more andthe same or different for appropriate organic compounds. For purposes ofthis invention, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valencies of the heteroatoms. Thisinvention is not intended to be limited in any manner by the permissiblesubstituents of organic compounds.

Examples of substituents include, but are not limited to, alkyl, aryl,aralkyl, cyclic alkyl, heterocycloalkyl, hydroxy, alkoxy, aryloxy,perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl,heteroaralkoxy, azido, amino, halogen, alkylthio, oxo, acyl, acylalkyl,carboxy esters, carboxyl, carboxamido, nitro, acyloxy, aminoalkyl,alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino,aralkylamino, alkylsulfonyl, carboxamidoalkylaryl, carboxamidoaryl,hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl,alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like.

As used herein, the term “network” refers to a three dimensionalsubstance having oligomeric or polymeric strands interconnected to oneanother by crosslinks.

As used herein, the term “strand” refers to an oligomeric or polymericchain of one monomer unit, or an oligomeric or polymeric chain of two ormore different monomer units.

As used herein, the term “backbone” refers to the atoms and bondsthrough which the monomer units are bound together. As used herein, theterm “prepolymer” refers to oligomeric or polymeric strands which havenot undergone crosslinking to form a network.

As used herein, the term “crosslink” refers to a connection between twostrands. The crosslink may either be a chemical bond, a single atom, ormultiple atoms. The crosslink may be formed by reaction of a pendantgroup in one strand with the backbone of a different strand, or byreaction of one pendant group with another pendant group. Crosslinks mayexist between separate strand molecules, and may also exist betweendifferent points of the same strand.

As used herein, the term “active substance” refers to a compound ormixture of compounds which causes a change in a biological substrate.Exemplary classes of active substances in the medical and biologicalarts include therapeutic, prophylactic and diagnostic agents. The activesubstance may be a small molecule drug, a vitamin, a nutrient, abiologic drug, a vaccine, a protein, an antibody or other biologicalmacromolecule. The active substance may be a mixture of any of the abovelisted types of compounds.

“Immunosuppressive agent” refers to an agent that inhibits or preventsan immune response to a foreign material in a subject. Immunosuppressiveagents generally act by inhibiting T-cell activation, disruptingproliferation, or suppressing inflammation.

As used herein, the terms “oligomer” and “polymers” each refer to acompound of a repeating monomeric subunit. Generally speaking, an“oligomer” contains fewer monomeric units than a “polymer.” Those ofskill in the art will appreciate that whether a particular compound isdesignated an oligomer or polymer is dependent on both the identity ofthe compound and the context in which it is used.

One of ordinary skill will appreciate that many oligomeric and polymericcompounds are composed of a plurality of compounds having differingnumbers of monomers. Such mixtures are often designated by the averagemolecular weight of the oligomeric or polymeric compounds in themixture. As used herein, the use of the singular “compound” in referenceto an oligomeric or polymeric compound includes such mixtures.

As used herein, reference to any oligomeric or polymeric materialwithout further modifiers includes said oligomeric or polymeric materialhaving any average molecular weight. For instance, the terms“polyethylene glycol” and “polypropylene glycol,” when used withoutfurther modifiers, includes polyethylene glycols and polypropyleneglycols of any average molecular weight.

As used herein, the term “Michael acceptor” refers to a functional grouphaving a carbon-carbon double or triple bond in which at least one ofthe carbon atoms is further bonded to a carbonyl group or carbonylanalogs such as imine, oxime, and thiocarbonyl. The reaction between aMichael acceptor and nucleophile results in the formation of a covalentbond between the nucleophile and the carbon atom not directly connectedto the carbonyl group or carbonyl analog. The reaction between a Michaelacceptor and a nucleophile may be called a “Michael addition.”

The term “aliphatic group” refers to a straight-chain, branched-chain,or cyclic aliphatic hydrocarbon group and includes saturated andunsaturated aliphatic groups, such as an alkyl group, an alkenyl group,and an alkynyl group. In one embodiment, alkyl groups are C1-C8 alkylgroups. In one embodiment, alkenyl groups are C2-C8 alkenyl groups. Inone embodiment, alkynyl groups are C2-C8 alkynyl groups.

The term “alkoxy” refers to an alkyl group, as defined above, having anoxygen atom attached thereto. In one embodiment, alkoxy groups are —O C1C8 alkyl groups. Representative alkoxy groups include methoxy, ethoxy,propyloxy, and tert-butoxy. An “ether” is two hydrocarbons covalentlylinked by an oxygen.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur atom attached thereto. In some embodiments, the “alkylthio”moiety is represented by one of —S-alkyl, —S-alkenyl, and —S-alkynyl. Insome embodiments, the “alkylthio” moiety is represented by one of—S—C1-C8 alkyl, —S—C2-C8 alkenyl, and —S—C2-C8 alkynyl. Representativealkylthio groups include methylthio and ethylthio.

The term “amido” is art-recognized as an amino substituted by a carbonylgroup.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group. The term “heteroaralkyl”, as used herein, refers toan alkyl group substituted with a heteroaryl group.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Examplary heteroatoms are nitrogen, oxygen, andsulfur.

As used herein, the term “thiol” means —SH; the term “hydroxyl” means—OH; and the term “sulfonyl” means —SO₂—.

As used herein the term “oxo” refers to a carbonyl oxygen atom.

As used herein, the term “alkaloid” refers to a naturally occurringorganic compound containing at least one non-peptidic nitrogen atom.

EXAMPLES

The following examples are intended to illustrate certain embodiments ofthe present invention, but do not exemplify the full scope of theinvention.

Example 1—Elliptical Ring Design

Polycaprolactone (PCL) was chosen as the loadable polymeric component ofthe structures due to its mechanical and physicochemical properties,unless otherwise stated. PCL is a degradable polyester with a lowmelting point of around 60° C. allowing multiple processingtechnologies. It is slowly degraded by hydrolysis of its ester linkagesin physiological conditions, making it an appropriate material for thepreparation of certain embodiments of long-term in vivo residentstructures. It has been used for controlled release and targeteddelivery of a variety of drugs.

Various flexible materials were tested for use as a flexible linker.Properties assessed included the ability to undergo 180 degreedeformation without breaking, ability to remain in the deformed statefor a prolonged period of time such as would occur in a stored pill, andability to recoil nearly 100% to the original shape. To maximize themechanical properties while maintaining biocompatibility, an isocyanatecrosslinked polyurethane generated from low-molecular weightpolycaprolactone monomers was used.

One such implementation consisted of addition of a 6:1.3:0.027:9.5 molarratio of polycaprolactone diol (MW 530 g/mol): polycaprolactone triol(MW 900 g/mol): linear high molecular weight polycaprolactone (MW 45,000g/mol): hexamethylene di-isocyanate. The first three ingredients werefirst mixed at 70 degrees Celsius until well mixed. The mixture wassonicated to remove entrapped air bubbles. The isocyanate as added andmixed for about 30 minutes while maintaining the temperature between70-75 degrees Celcius. While maintaining temperature, the prepolymersolution was gently pipetted into PDMS molds of the desired shape. Thethermoset was set at 70-75 degrees Celsius for 48 hours at which pointthe shape is firmly set and minimal residual free isocyanate is present.

FIG. 3 shows an elliptical ring structure configured for gastricresidence. The elliptical ring structure comprises a loadable polymericcomponent and one or more linkers configured for controlled degradationincorporated into the elliptical ring structure. FIG. 3A shows anelliptical ring structure next to a 000-size capsule. The ellipticalring structure has a major axis diameter greater than about 40 mm and aminor axis diameter comparable to the major axis of the 000-size capsule(i.e., about 26 mm). In FIG. 3B, the elliptical ring structure is shownpacked into (and bent within) the 000-size capsule. In FIGS. 3C-3D,controlled degradation linkers, which are incorporated into theelliptical ring structure at points along the minor axis, are visible.In FIG. 3D, the elliptical ring structure is twisted such that the axisof the helix is along the minor axis of the elliptical ring structure.The gains of packing efficiency can be seen in FIG. 3E as compared toFIG. 3B.

Example 2—Multi-Armed Star Design

Design constraints were addressed by using a combination of relativelyrigid elements (loadable polymeric components) as drug matrix thatprovide mechanical stability and flexible recoil elements (elasticpolymeric components.) As shown in FIGS. 4A-5B, two geometric familiesof rigid and flexible elements were studied in greater detail, a“polygon” family of alternating rigid and flexible elements which foldon itself and a “stellate” family in which rigid elements project from acentral flexible element. Designs which could be efficientlyencapsulated into a standard size 000 gelatin capsule were generated inInventor CAD software, 3D printed, and used as positives to make PDMSnegative molds. Versions optimized for capsules of other sizes,including larger veterinary capsules, as well as smaller capsules formore ready human consumption including 00-EL, 0-EL were also developed.

In FIG. 4A, the structure comprises a central core and six radialprojections, shown next to a 000-size capsule. The central corecomprises an elastic polymeric component comprising elastic PCL, and theprojections comprise a rigid loadable polymeric component. Eachprojection has a length equal to just less than the length of thecapsule such that the unencapsulated final form has a circumscribingdiameter equal to nearly twice the capsule length. In FIG. 4B, variousstructures with radial projections having sector shapes with internalsector angles equal to approximately 360°/N are shown. Each structurehas projections of 20-mm length within a circumscribing diameter ofabout 44 mm. For a structure with three radial projections, the designsurface was 915 mm² and the design volume was 438 mm³. For a structurewith four radial projections, the design surface was 1047 mm² and thedesign volume was 723 mm³. For a structure with six radial projections,the design surface was 1410 mm² and the design volume was 954 mm³. For astructure with eight radial projections, the design surface was 1658 mm²and the design volume was 1015 mm³. In FIG. 4C, three structures withfour, six, and eight radial projections, respectively, are shown packedin capsules and in their unencapsulated forms. The projections areformed from at least one material with a high elastic modulus toincrease the resistance to compression and duration of gastricresidence.

Table 1 summarized the various sizes of the structures.

TABLE 1 capsule capsule w = folded Design Design N = length a = edgewidth structure Circumscribing volume surface Arms (mm) length (mm) (mm)width (mm) radius (mm) = R (mm{circumflex over ( )}3) (mm{circumflexover ( )}2) 3 26 20 9.9 8.5 ~44 438 915 4 26 20 9.9 8.5 ~44 723 1047 526 20 9.9 8.5 ~44 6 26 20 9.9 8.5 ~44 954 1410 7 26 20 9.9 8.5 ~44 8 2620 9.9 8.5 ~44 1015 1658

Example 3—Polygonal Design

In FIG. 5A, an embodiment with a hexagonal structure is shown next to a000-size capsule. The vertices of the hexagon comprise elastic polymericcomponents, and the sides of the hexagon comprise rigid loadablepolymeric components. Each side has a length equal to just less than thelength of the capsule such that the unencapsulated final form has acircumscribing diameter equal to nearly twice the capsule length. FIG.5B, various structures with radial projections having sector shapes withinternal sector angles equal to approximately 360°/N are illustrated.Four embodiments with square, hexagonal, octahedral, and dodecahedralstructures, respectively, are shown in their unencapsulated forms. Theshapes are formed from at least one material with a high elastic modulusto increase the resistance to compression and duration of gastricresidence.

Each side of each polygon is about 22-mm long, and each folded polygonalstructure has a width of about 8.5 mm. For a structure with four sides,the circumscribing diameter was about 15.6 mm, the design surface wasabout 964 mm², and the design volume was about 640 mm³. For a structurewith six sides, the circumscribing diameter was about 22.0 mm, thedesign surface was about 1451 mm², and the design volume was about 998mm³. For a structure with eight sides, the circumscribing diameter wasabout 28.8 mm, the design surface was about 1806 mm², and the designvolume was about 1125 mm³. For a structure with ten sides, thecircumscribing diameter was about 35.6 mm, the design surface was about2052 mm², and the design volume was about 1148 mm³. For a structure withtwelve sides, the circumscribing diameter was about 42.5 mm, the designsurface was about 2389 mm², and the design volume was about 1208 mm³.The sizes are summarized in Table 2.

TABLE 2 Implied w = folded polygon capsule capsule structurecircumscribing Design Design N = length a = edge width width radius (mm)R = volume surface Edges (mm) length (mm) (mm) (mm) a/2sin(pL/N)(mm{circumflex over ( )}3) (mm{circumflex over ( )}2) 4 26 22 9.9 8.515.6 640 964 6 26 22 9.9 8.5 22 998 1451 8 26 22 9.9 8.5 28.8 1125 180610 26 22 9.9 8.5 35.6 1148 2052 12 26 22 9.9 8.5 42.5 1208 2389

Example 4—Ingestion of Structures

FIG. 6 is a series of chest/abdominal X-ray images obtained in a largeanimal model at 3 minutes, 5 minutes, and 12 minutes respectively afteringestion, demonstrating deployment of a multi-armed structure from acapsule and in vivo adoption by the structure of the native conformationover about 12 minutes.

Similarly, FIG. 7 includes a series of chest/abdominal X-ray imagesobtained in a large animal model after ingestion of a hexagonalretention/delivery structure, the sides formed with polycaprolactone andthe vertices comprising enteric elastomer linkers, in accordance withsome embodiments. Each retention/delivery structure was packed tightlyinto a 000 capsule and expanded to its native shape after reaching agastric cavity. FIG. 7A is an image taken after ingestion when thesubject was fasting, and FIG. 7B is an image taken five days afteringestion when the subject was eating a regular diet. Table 3 presentsthe results of eight trials in six different pigs using the hexagonalretention/delivery structure according to some embodiments. As shown inthe table in FIG. 7, the structure was successfully retained in thegastric cavity in all cases on Day 0 and Day 2, and in three cases, onDay 5. In the five other cases on Day 5, the enteric elastomer linkersdegraded, and the structure passed safely through the gastrointestinaltract.

TABLE 3 Day 0 Day 2 Day 5 Gastric cavity retention 8/8 8/8 3/8Dissolution of linker and 0/8 0/8 5/8 safe passage Adverse events 0/80/8 0/8

8 Trials in 6 Different Pigs of a Hexagonal Structure with EntericLinkers Example 5—Enteric Elastomers

FIG. 8 is a schematic representation of an enteric elastomer and amethod of preparing an enteric elastomer in accordance with someembodiments. In FIG. 8A, a polymer gel network is illustrated with afirst set of lines representing synthesized poly(acryloyl-6-aminocaproicacid); a second set of lines representing linear poly(methacrylicacid-co-ethyl acrylate) (e.g., EUDRAGIT® L 100-55, available from EvonikIndustries AG (Essen, Germany)); a plurality of boxes representinghydrogen bonds between polymer chains; and spots representing watermolecules. In FIG. 8B, a manufacturing process flow is illustrated. Fromthe left of FIG. 8B, a poly(acryloyl-6-aminocaproic acid) sodium saltwater solution and a poly(methacrylic acid-co-ethyl acrylate) sodiumsalt water solution were mixed with one of various ratios (including,but not limited to 1:0, 1:1, and 1:2), into a homogeneous polymer sodiumsalt water solution. Then, two polymers were co-precipitated upon theaddition of HCl solution. Precipitates of polymer complexes weretransformed into an enteric, elastic polymer gel, recovered at thebottom of the centrifuge tube. The formed enteric elastomer could be cutand/or pressure molded into various shapes for the construction ofstructures, mechanical characterizations, etc.

In FIG. 8C, three optical images of stretch testing of an entericelastomer are shown. The enteric elastomer had a 1:2 ratio ofpoly(acryloyl-6-aminocaproic acid) to poly(methacylic acid-co-ethylacrylate). The top image shows an enteric elastomer, 1.5 cm long beforestretching. The middle image shows the enteric elastomer stretched tothree times its initial length. The bottom image shows the entericelastomer five minutes after the external force was removed and theenteric elastomer had returned to its initial length.

FIG. 9 illustrates the morphology, mechanical, dissolution, andcytotoxicity characterizations of three formulations of entericelastomers in accordance with some embodiments. In FIG. 9A, a series ofscanning electron microscope (SEM) images show the morphology of driedenteric elastomers with three different ratios ofpoly(acryloyl-6-aminocaproic acid) (PA6ACA) to EUDRAGIT® L 100-55 (L100-55), 1:0, 1:1, and 1:2 respectively. The scale bar in the images isequal to 50 μm. All three formulations of enteric elastomers have porousstructures, but higher concentrations of EUDRAGIT® L 100-55 correlatedwith decreasing pore size. The formulations were dried by lyophilizationfor 48 hours to measure their water content. The water content decreasedfrom 31.6 wt % in pure poly(acryloyl-6-aminocaproic acid), to 27.7 wt %of the enteric elastomer with the 1:1 ratio, and to 26.4 wt % of theenteric elastomer with the 1:2 ratio, consistent with the SEMobservations.

To test the elastic properties of the enteric elastomers, tensile stresstesting was conducted. In FIG. 9A, a series of corresponding truestress-true strain plots for the enteric elastomers are presented. TheYoung's modulus and tensile strength increases with increasing amountsof EUDRAGIT® L 100-55, while the strain reduces from 857% ofpoly(acryloyl-6-aminocaproic acid) itself to 341% of the entericelastomer with the ratio 1:2.

After demonstrating the elastic properties of the enteric elastomers,their enteric ability was evaluated by dissolution testing in simulatedgastric fluid and simulated intestinal fluid. In FIG. 9B, a plotcompares the results of corresponding dissolution tests of the entericelastomers in simulated gastric fluid and simulated intestinal fluid.Poly(acryloyl-6-aminocaproic acid) showed long-term stability insimulated gastric fluid without distinguishable mass loss for over 4days. In contrast, within the same period of time,poly(acryloyl-6-aminocaproic acid) dissolved in simulated intestinalfluid with pH of 6.8.

To demonstrate the biocompatibility and safety ofpoly(acryloyl-6-aminocaproic acid) after being dissolved, thepoly(acryloyl-6-aminocaproic acid) sodium salt was tested forcytotoxicity in HeLa cells at a range of concentrations. In FIG. 9C, aplot compares the results of corresponding cytotoxicity studies of theenteric elastomer formulations in the HeLa cells. After a 24-hourincubation, no significant cytotoxicity was observed forpoly(acryloyl-6-aminocaproic acid) over a range of concentrations from0.0001 mg/mL to 5 mg/mL. The observed cytotoxicity at high concentration(above 5 mg/mL) may be due to a change in pH of the cell culture mediumafter dissolving the polymer sodium salt. Therefore,poly(acryloyl-6-aminocaproic acid) can be biocompatible.

In order to evaluate the stability of an enteric elastomer in vivo, acircle composed of polycaprolactone (PCL) arcs with intervening entericelastomer linkers was made according to some embodiments. FIG. 10illustrates the construction and in vivo evaluation of the ring-shapedgastric residence structure in accordance with some embodiments. In FIG.10A, six pieces of enteric elastomer were fitted into a ring shapedpolydimethylsiloxane (PDMS) mold with an outer diameter of 3.0 cm, innerdiameter of 2.8 cm, and depth of 0.2 cm. After the elastic entericpolymer gels were dried by vacuum, FIG. 10B shows the placement of apolycaprolactone (PCL) beads in between the six pieces of entericelastomer. After PCL was melted and solidified, FIG. 10C shows aring-shaped structure removed from the mold and illustrates a method offolding the structure to reach the result shown in FIG. 10D. In FIG.10E, the folded structure has been packed into a gelatin capsule with alength of 2.6 cm and diameter of 0.9 cm. FIGS. 10E-G are lateral andanteroposterior X-ray images, respectively, of a pig after administeringthe gelatin capsule containing the ring-shaped structure (radiopaquemetal balls were embedded in the PCL segments for imaging). After thering shaped structure in the capsule was delivered to a pig through itsesophagus, the capsule was dissolved in the stomach and the ring-shapedstructure was released and recovered its shape.

Example 6—Formation of Linkers

Enteric linker elements were formed by compressive molding. In oneembodiment, Eudragit L100-55 (Evonik), an enteric material known to theart to have a pH-dependent dissolution profile, was blended with aplasticizer (triacetin) in a ratio of between 60:40 and 80:20. 3 g ofthe resulting mixture was placed between two 6×6 inch Teflon sheets andplaced on a hot press at 110-120 degrees Celsius and compressed to 5000psi for 20 minutes. The Teflon sheets were removed from the press andquenched in room temperature tap water briefly for 10 seconds, afterwhich the Eudragit film was removed.

Linkers with other dissolution profiles were generated in a similarfashion. Eudragit RS PO (Evonik), a water soluble polymer with a timedependent dissolution profile, was blended with a plasticizer(triacetin) at ratios of 70:30 to 85:15, and compressively molded in asimilar fashion on a hot press at 100-110 degrees Celsius and 3000 psifor 10-20 minutes.

In some cases, other water soluble polymers such asvinylpyrrolidone-vinyl acetate copolymers (e.g., KOLLIDON® VA 64 (BASF)and KOLLIDON® SR), polyvinylpyrrolidone, cellulose acetate,hydroxypropyl methyl cellulose, or polyvinyl alcohol were compressivelymolded or cast into films by solvent (for example, water) evaporation togenerate sheets of material for use as linkers.

The time- or pH-dependent linkers can be interfaced with the drug loadedpolycaprolactone matrix. Several strategies to achieve this werecontemplated. In one case, films of the elastic PCL prepolymer solutionwere painted onto both sides of the dissolution film and cured. In thecase of Eudragit L100-55, this provided covalent crosslinking of theelastic PCL to the dissolvable linker via urethane linkage formationwith available reactive groups. The multilayer film produced in this wayhad an outer interface of elastic PCL and could be interfaced withlinear PCL through a final application of heat for a period of time in aconstraining mold.

In another example, biocompatible adhesives were used to interface thedissolution linkers with polycaprolactone. In one case, sheets ofpolycaprolactone film are generated to facilitate interfacing. Using aplasticizer (Pluronic P407) at 10% w/w ratio with polycaprolactonegenerally improved the flexibility and reduced brittleness of thepolycaprolactone films. Films of polycaprolactone were adhered on eitherside of the pre-formed dissolution film using biomedical adhesives suchas a urethane (e.g., Loctite® M-11FL™ Hysol® Medical Structure UrethaneAdhesive) or a cyanoacrylate (e.g., Loctite® 3981 Hysol® EpoxyStructural Adhesive).

Linkers with appropriate geometry were then cut from the multilayeredfilms whose exposed outer layers are polycaprolactone. These could beinterfaced with the drug loaded polycaprolactone matrix readily with anapplication of heat at the interface.

Example 7—Mechanical Characterization of Elastic Polymers

The PCL elastomer was mechanically characterized using tension,compression, and creep loading. Mechanical characterization wasconducted according to ASTM standards D638 (tension), D575(compression), and D2990 (Creep).

Tension

The PCL elastomer was cured into a polymer sheet 2 mm in thickness. Thesheet was allowed to cool and a standard dumbbell die (ASTM D-638) wasused to cut specimens from the sheet. Specimens were loaded into gripsof an Instron testing machine and the gauge length measured using adigital micrometer. Displacement was applied to the specimen at a rateof 10 mm/min until samples ruptured. Force was converted into normalstress (F/A) and displacement into strain (ΔL/L) and is plotted in FIG.11A.

Compression

The PCL elastomer was cured into a slab 13 mm in thickness. The slab wasallowed to cool and a rotating hollow drill bit was used to cut a 28 mmdiameter specimen from the slab. Specimens were placed into aconstrained loading compression jig and subjected to displacement at 12mm/min. Specimens were tested until reaching 30% compression strain.Force was converted into pressure (F/A) and displacement into a volumeratio (ΔV/V) and is plotted in FIG. 11B.

Creep

PCL elastomer, polydimethylsiloxane (silicone), and poly ethylene vinylacetate (PEVA) were cured into a polymer sheets 2 mm in thickness. Thesheets were allowed to cool and a standard dumbbell die (ASTM D-638) wasused to cut specimens from the sheets. Specimens were loaded into gripsof an Instron testing machine and the gauge length measured using adigital micrometer. A constant stress corresponding to 30% of theultimate tensile strength of each material was applied to the specimensfor 60 min. The force and displacement were calculated throughout thetest and converted into normal stress (F/A) and strain (ΔL/L) and isplotted in FIG. 11C.

Example 8—Finite Element Analysis of Retention Structure

The finite element method was used to analyze the stress and strainprofiles of structures in SIMULIA Abaqus FEA software. The geometry ofstructures was imported into Abaqus from AutoDesk Inventor. The materialproperties of the PCL elastomer were defined using the Mooney-Rivlinhyperelastic model from tension and compression tests mentioned above.The linear PCL arms were assumed to be linear elastic and the moduluswas derived from flexural tests described above. The model was meshedusing C3D4 elements and the PCL elastomer and linear PCL were bonded atinterfaces. A 1 mm diameter plate was introduced to the bottom of thePCL elastomer to hold the structure in place throughout deformation.Force was perpendicularly applied to the top of each arm to simulatefolding of the structure into a capsule. Following computation the vonMisses, maximum principle, longitudinal, and laterial stresses wereanalyzed. Results of the finite element modelling are shown in FIG. 12.

Example 9—Simulated Pyloric Exit of Retention Structure

A custom experimental setup was developed to better understand transitof retention structures through the pylorus. A schematic of theexperimental setup is shown in FIG. 13A. A 20 cm upper diameter by 2 cmlower diameter polypropylene funnel was used to simulate the pyloricsphincter. Structures having a stellate shape as described above wereplaced into the funnel and a custom-designed plunger was used to pushthe structure through the 2 cm spout. The plunger was attached to thetension cross-head of an Instron testing machine and the funnel to aclamp. The structure was pushed through the funnel at a rate of 10mm/min and the force and displacement were captured throughout the test,and is shown in FIG. 13B.

Example 10—Evaluation of Gastric Retention In Vivo

To assess particular formulations that were developed for ability toachieve gastric retention, the structures (e.g., hexagonal and stellate)as described above were administered to a large animal model, 35-50 kgYorkshire pigs. This model was chosen as it is known to have gastricanatomy similar to humans and is widely used in evaluating structures inthe gastrointestinal space. The prolongation of food bolus passage inthe pig is generally measured in hours, and as such, for evaluation ofretention on the order of days this should introduce no more than asmall error while providing a good model of gastric anatomy and gastricexit.

Pigs were sedated with Telazol and Xylazine, or in some cases withketamine, or in some cases isoflurane, and an endoscopic overtube wasplaced in the esophagus under endoscopic visual guidance duringesophageal intubation. Gelatin capsules containing the structures wereadministered via overtube into the esophagus and/or stomach and theovertube was removed. Serial x-rays were obtained immediately afterwardsto document the process of deployment from the gelatin capsule. Bloodsamples, if necessary, were obtained via cannulation of a mammary veinon the ventral surface of the pig at indicated time points, most oftentime 0 (prior to administration of the pill), 5 min, 15 min, 30 min, 2hours, 6 hours, and then daily for a minimum of 5 days and then threetimes per week. Three times per week, chest and abdominal radiographswere obtained from a minimum of 5 views including anteriorposterior,left lateral and right lateral positions of the chest, upper abdomen,and lower abdomen and rectum. Between 3 and 5×1 mm steel fiducials wereembedded via melt casting into the drug delivery PCL arms. These couldbe tracked radiographically to assess deployment and intactness of thedelivery system (configuration), as well as location in the gastriccavity or upper or lower abdomen. Radiographs were also assessed forpresence of evidence of complication including pneumoperitoneum orintestinal obstruction. Exemplary radiographs are shown in FIGS. 6 and7).

Example 11—Evaluation In Vitro of Drug Stability and Release

Stability of drugs in the gastric environment was evaluated using HPLCand LC-MS/MS analysis. Hydrophilic drugs were dissolved in simulatedgastric fluid (SGF, 0.2% (w/v) NaCl, 0.83% (v/v) HCL, pH=1) incentrifuge tubes. Hydrophobic drugs were dissolved in IAW (isopropanol70%, acetonitrile 20%, water 10%) with pH adjusted to 1 using HCL. As acontrol, drugs were dissolved in the same solvents with pH adjusted to6.0 (using 1M NaOH). After vortexing for 1 min and sonication for 10min, tubes were placed in a shaking incubator (150 rpm, 37° C.). Sampleswere collected at defined time points for up to two weeks and analyzedby HPLC and LC-MS/MS to quantify the stability of drugs.

Stability of drugs loaded into PCL based delivery matrices were alsostudied. Loading of drugs is described below in Examples 16 and 17. Drugloaded structures were kept at acidic conditions (pH=1, 37° C.) and atdefined intervals, drug was extracted from the PCL matrix and analyzedby HPLC and/or LC-MS/MS. In order to extract drugs, structures weresonicated in SGF (hydrophilic drugs) or isopropanol (hydrophobic drugs)for 10 min. Fresh drug in SGF or Isopropanol was prepared immediatelybefore analysis as controls.

Stability of Doxycycline (Hydrophilic) in SGF (pH=1, 37° C.)

Stability of Doxycycline in SGF (pH=1, 37° C.) over two weeks analyzedby HPLC is shown in FIG. 14. An Agilent 1260 infinity model HPLC systemequipped with an autosampler and a C8 reversed phase column (4.6×150-mm,i.d., 5-um particle size) was used. The mobile phase was ACN/water+0.1%formic acid pH 3.5 (60/40). 20 μl of samples was injected to the columnat a mobile phase flow rate of 1 mL/min and the UV absorption at 350 nmwas recorded over 10 min.

Stability of Artemether (Hydrophobic) in IAW (pH=1, 37° C.)

Stability of Artemether in IAW (pH=1, 37° C.) over two weeks analyzed byHPLC is shown in FIG. 15. The area under curve (AUC) associated with thedrug was used to quantify the stability percentage.

Stability of Ivermectin in Solution or in PCL Structures in AcidicConditions (pH=1, 37° C.)

Free Ivermectin is unstable in acidic conditions (IAW, pH=1, 37° C.) isshown in FIG. 16A. PCL structures protected ivermectin against acidicdegradation. Ivermectin (IVM) loaded structures, shown in FIG. 16B, wereplaced in SGF+RH solution (pH=1, 37° C.) for 72 h. Drug was extracted bysonicating the structure in isopropanol for 10 min. The HPLCchromatogram of extracted IVM was similar to that of fresh IVM dissolvedin isopropanol, indicating that PCL structures protected IVM in acidicenvironment.

Example 12—In Vitro Drug Release Studies

Drug loaded oral delivery structures with varying compositions wereprepared as described in Examples 16 and 17. Structures loaded withhydrophilic drugs were placed in sealed cups with 100 mL of SGF. Forhydrophobic drugs, Kolliphor® RH40, a non-ionic oil-in-watersolubilizing agent, was added to SGF (0.25% (w/v)) to increase thesolubility of released drugs. The cups were placed in a shakingincubator (150 rpm, 37° C.). Samples were collected at defined timepoints for up to two weeks and analyzed by HPLC and LC-MS/MS to quantifythe amount of drug released.

In Vitro Release of Doxycycline (Hydrophilic) Loaded Structures in SGF

FIG. 17A shows the in vitro release of doxycycline loaded PCL stars inSGF (pH=1, 37° C.): Pluronic P407, a hydrophilic surfactant, was addedto the PCL matrix to facilitate drug suspension in the polymer matrixand to tune the release kinetics. Drug concentration in the releasemedia was measured by HPLC. The ratio of PCL:PLu:Dox is expressed as wt% in the figure legend.

In Vitro Release of Ivermectin (Hydrophobic) Loaded Structures inSGF+RH40

FIG. 17B shows in vitro release of Ivermectin (IVM) loaded star-shapedstructures with different formulations in SGF+RH40 (pH=1, 37° C.).Different excipients, i.e., RH40, Pluronic P407, and Soluplus, wereadded to tune the release kinetics, as shown in Table 4. Drugconcentration in the release media was measured by HPLC.

TABLE 4 Batch PCL IVM RH40 P407 Soluplus 1 55 20 20 5 2 60 20 20 3 65 2010 5 4 70 20 10 5 70 20 10 6 55 20 5 20 7 65 20 5 10

FIG. 17C shows in vitro release of Ivermectin (IVM) loaded star-shapedstructures with different formulations in SGF+RH40 (pH=1, 37° C.). Allformulations include 70% PCL, 20% IVM, and 10% excipient. Excipientsinclude 4-arm and 8-arm branched PEG, and Pluronic P407. For “premelt”sample, IVM and PEG8 were premelted before mixing and re-melting withPCL. Drug concentration in the release media was measured by HPLC. Errorbars represent SD of three independent replicates.

Example 13—Flexural Properties of Drug-Loaded PCL Segments

Linear PCL was mechanically characterized in flexion according to ASTMstandard D790, and shown in FIG. 18. Sheets of linear PCL, PCL withexcipients, and PCL with excipients and drugs were cured into sheets 2mm in thickness. The sheets were allowed to cool and then rectangles 80mm length×8 mm width were cut out of the sheet to produce samples. Adigital micrometer was used to measure the width and thickness ofspecimens prior to testing. An Instron testing machine fitted with athree-point bending fixture was used to test specimens. The test wasconducted at a rate of 0.85 mm/min and a span of 32 mm was used for allspecimens. The test was stopped when specimens failed or when theyreached a flexural stain of 20%. Force was converted into flexuralstress and displacement into flexural strain.

Example 14—Gastric Residence Times

FIGS. 19-21 show histograms of the probability of gastric retention atspecified time points of three different configurations of gastricresidence systems. Gastric residence systems were formed with inclusionof stainless steel 1 mm fiducials placed in the polymeric drug delivery“arms” during polymerization of the arms. Gastric residence systems wereadministered to Yorkshire swine (35-50 kg) under sedation and through aendoscopic overtube into the gastric cavity. Serial radiographs wereobtained in multiple positions (anteroposterior, left lateral, rightlateral) of the chest, abdomen, and pelvis. Radiographs were taken afterdelivery for up to 15 minutes to confirm deployment from the outercapsule and/or restraining system. Radiographs were then obtained dailyfor the next 4 days and three times weekly after the first 5 days.Location of the residence system in the gastric cavity was confirmedfrom multiple radiographic views. (FIG. 19, H1-EE1) Hexagonal residencesystem with polycaprolactone “arms” and elastic elements at verticesmade from enteric elastomer. (FIG. 20, H1-F1-F1-X1) Hexagonal residencesystem with arms made of isocyanate crosslinked polycaprolactone andelastic element made from isocyanate crosslinked polycaprolactone andwith dissolvable linkers made of Eudragit L100-55 films. (FIG. 21,H1-F1-R1-X2) Hexagonal residence system with arms made ofpolycaprolactone and elastic elements made from isocyanate crosslinkedpolycaprolactone and dissolvable linkers made of a blend of 90% EudragitL100-55 and 10% poly(acrylic acid).

Example 15—Passage of Food

Intra-gastric balloons (a gastric resident system which is deployedendoscopically) for the treatment of obesity has noted symptomsconsistent with partial gastric outlet obstruction, specifically ofnausea in the range of 18-90% of patients. To monitor the potential forgastric outlet obstruction in residence structures described herein,these structures were evaluated in a large animal model. Specifically astructure constructed primarily of non-degradable elastic polymericcomponents was prepared in a stellate configuration to observe potentialoutlet obstruction. This was deployed in the stomach of a ˜50 kg pigwhich was monitored clinically twice a day for evidence ofgastrointestinal obstruction including abdominal distension, vomitingand decreases feces production. Furthermore, serial x-rays wereperformed 3 times a week to evaluate for evidence of obstructionincluding gastric distension. Moreover at day 35 the animal was placedon a liquid diet for 24 hours prior to the endoscopic procedure toevaluate the animal's capacity for gastric emptying and the stomachevaluated endoscopically. On endoscopic imaging the structure was notedto overly the pylorus and the gastric cavity was devoid of food materialsupporting the capacity of the structure to allow for passage of foodout of the stomach and yet remain resident in the stomach cavity andeven overlying the pylorus.

FIG. 22 shows endoscopic evaluation at day 35 of retention of a stellatedelivery system. In the image the delivery system is overlying thepylorus and a probe is in the field. As noted in the picture thereappears to be no significant evidence of retained food and in fact theprototype is free of any entangled food particulates.

Example 16—In Vivo Extended Oral Doxycycline Delivery

Doxycycline hyclate 100 mg commercially available tablets were purchasedfrom a veterinary source (Patterson Veterinary). One tablet each wasadministered on Day 0 to three pigs and serum was collected from venouscannulation at the selected time points. Separate pigs were administered6-armed star formulations of doxycycline totaling approximately 1000 mgintended to provide the same dosage as 100 mg twice daily for about 5days. Doxycycline was formulated at 25% w/w loading in polycaprolactone45,000 MW along with 4% w/w Pluronic P407 hydrophilic excipient. Theblend was melted and mixed at 75 degrees Celsius and cast into PDMSmolds. The central portion was removed from the star after cooling andelastic PCL prepolymer solution was poured into the central void andcured for 48 hours at approximately 75 degrees Celsius. The resultingshapes were encapsulated and administered to the Yorkshire pigs aspreviously described. Drug levels were quantified using LC/LC-MS, asshown in FIG. 24.

Example 17—In Vivo Extended Oral Ivermectin Delivery

Ivermectin was dissolved in a 50:50 solution of EtoH and water and 0.2mg/kg was administered to each 40-50 kg pig as an oral gavage in 10 mlof solution. Blood specimens from peripheral venous cannulation werecollected in serum separator tubes at the indicated times before andafter administration and centrifuged. Serum was frozen in aliquots forlater batch analysis. Serum levels of ivermectin were measured on aWaters LC-MS using standard methods, as shown in FIG. 25A.

Ivermectin was loaded into polycaprolactone by first mixing ivermectinat 20% (w/w) of final mass with 10% (w/w) of the final mass PluronicP407 poloxamer and briefly melting at 75 degrees celcius.Polycaprolactone 45,000 molecular weight (Sigma-Aldrich, St. Louis, Mo.)was then added (70% w/w) and the mixture was melted at 75 degrees C. for20 minutes and mixed for 5 minutes. The molten mixture was transferredinto a mold of the stellate design. The mold was heated to 90 degreesCelsius for 2 hours then air-cooled. Arm portions were prepared andplaced back into the stellate mold leaving the central element as avoid. Elastic PCL prepolymer solution was poured into the centralelastic region and cured at 70 degree Celsius for 24 hours. Stellateshapes were removed from the mold and placed into 000 gelatin capsules.The capsules were administered via endoscopically placed esophagealovertube into the gastric cavity of sedated Yorkshire pigs. Threecapsules, each containing about 200 mg of ivermectin embedded in theformulation, were administered to each of three pigs. Results are shownin FIG. 25B.

The elastic element was made as described above in specially made moldscorresponding to the central elastic element. The ivermectin loadedelement was made as described above for in FIG. 25B. The molten mixturewas transferred into a mold of the stellate design into which thepreformed elastic central element had been placed in position. The moldwas heated to 90 degrees celcius for 2 hours then air-cooled. Stellateshapes were removed from the mold and placed into 000 gelatin capsules.The capsules were administered via endoscopically placed esophagealovertube into the gastric cavity of sedated Yorkshire pigs. Tencapsules, each containing about 200 mg of ivermectin embedded in theformulation, were administered to each of three pigs. Results are shownin FIG. 25C.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Other elements may optionallybe present other than the elements specifically identified by the“and/or” clause, whether related or unrelated to those elementsspecifically identified unless clearly indicated to the contrary. Thus,as a non-limiting example, a reference to “A and/or B,” when used inconjunction with open-ended language such as “comprising” can refer, inone embodiment, to A without B (optionally including elements other thanB); in another embodiment, to B without A (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc. As used herein in the specification andin the claims, “or” should be understood to have the same meaning as“and/or” as defined above. For example, when separating items in a list,“or” or “and/or” shall be interpreted as being inclusive, i.e., theinclusion of at least one, but also including more than one, of a numberor list of elements, and, optionally, additional unlisted items. Onlyterms clearly indicated to the contrary, such as “only one of” or“exactly one of,” or, when used in the claims, “consisting of,” willrefer to the inclusion of exactly one element of a number or list ofelements. In general, the term “or” as used herein shall only beinterpreted as indicating exclusive alternatives (i.e. “one or the otherbut not both”) when preceded by terms of exclusivity, such as “either,”“one of,” “only one of,” or “exactly one of.” “Consisting essentiallyof,” when used in the claims, shall have its ordinary meaning as used inthe field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively, asset forth in the United States Patent Office Manual of Patent ExaminingProcedures, Section 2111.03.

What is claimed is:
 1. A gastric residence structure comprising: aloadable polymeric component; an elastic polymeric component; and aseparate linker component, said linker connecting the loadable polymericcomponent with the elastic polymeric component; wherein the gastricresidence structure is configured to be folded and physicallyconstrained during administration and is configured to assume an openretention shape upon removal of a constraint, wherein change between thefolded shape and the open retention shape is mediated by the elasticpolymeric component that undergoes elastic deformation when theresidence structure is in the folded shape and recoils when the gastricresidence structure assumes the open retention shape, and wherein saidlinker degrades, dissolves, disassociates, or mechanically weakens in agastric environment which results in loss of retention shape integrityand passage out of a gastric cavity.
 2. The gastric residence structureof claim 1, wherein the loadable polymeric component comprises at leastabout 60 wt % of the total structure weight.
 3. The gastric residencestructure of claim 1, wherein the gastric residence structure has afolding force of at least about 0.2 N.
 4. The gastric residencestructure of claim 1, wherein the residence structure has an opencross-sectional dimension of at least about 2 cm.
 5. The gastricresidence structure of claim 1, wherein the residence structure isconfigured such that it is retained in the gastric cavity for at leastabout 24 hours.
 6. The gastric residence structure of claim 1, whereinthe loadable polymeric component comprises an active substance.
 7. Thegastric residence structure of claim 6, wherein the gastric residencestructure is configured such that the active substance is released fromthe loadable polymeric component at a particular initial average rate asdetermined over the first 24 hours of release, and wherein the activesubstance is released at an average rate of at least about 1% of theinitial average rate over a 24 hour period after the first 24 hours ofrelease.
 8. The gastric residence structure of claim 1, wherein the openretention shape is a multi-armed star shape.
 9. The gastric residencestructure of claim 1, wherein the elastic polymeric component comprisesa polymer selected from the group consisting of polyesters, polyethers,polysiloxanes, polyamides, polyacrylates, polymethacrylates,polyanhydrides, and polyurethanes.
 10. The gastric residence structureof claim 1, wherein the loadable polymeric component comprisespolycaprolactone (PCL), poly(ethylene-co-vinyl acetate), or polyethyleneglycol (PEG).
 11. The gastric residence structure of claim 1, whereinthe folded shape has a convex hull at least about 10% less than a convexhull of the open retention shape.
 12. The gastric residence structure ofclaim 1, wherein the folded shape has a largest cross-sectionaldimension at least about 10% less than a largest cross-sectionaldimension of the open retention shape.
 13. A method for delivering aresidence structure, comprising: administering to a subject a containingstructure containing a gastric residence structure as in claim
 6. 14.The method of 13, wherein the subject is a human.
 15. A gastricresidence structure comprising: a plurality of loadable polymericcomponents; and a central elastic polymeric component; wherein theplurality of polymeric components are each connected to the centralelastic polymeric component via a separate linker component, wherein thegastric residence structure is configured to be folded and physicallyconstrained during administration and is configured to assume an openretention shape upon removal of a constraint, wherein change between thefolded shape and the open retention shape is mediated by the elasticpolymeric component that undergoes elastic deformation when theresidence structure is in the folded shape and recoils when the gastricresidence structure assumes the open retention shape, and wherein saidlinker degrades, dissolves, disassociates, or mechanically weakens in agastric environment which results in loss of retention shape integrityand passage out of a gastric cavity.
 16. The gastric residence structureof claim 15, wherein the plurality of loadable polymeric componentscomprise at least about 60 wt % of the total structure weight.
 17. Thegastric residence structure of claim 15, wherein the gastric residencestructure has a folding force of at least about 0.2 N.
 18. The gastricresidence structure of claim 15, wherein the residence structure has anopen cross-sectional dimension of at least about 2 cm.
 19. The gastricresidence structure of claim 15, wherein the residence structure isconfigured such that it is retained in the gastric cavity for at leastabout 24 hours.
 20. The gastric residence structure of claim 15, whereinone or more of the plurality of loadable polymeric components comprisean active substance.
 21. The gastric residence structure of claim 20,wherein the gastric residence structure is configured such that theactive substance is released from the plurality of loadable polymericcomponents at a particular initial average rate as determined over thefirst 24 hours of release; and wherein the active substance is releasedat an average rate of at least about 1% of the initial average rate overa 24 hour period after the first 24 hours of release.
 22. The gastricresidence structure of claim 15, wherein the open retention shape is amulti-armed star shape.
 23. The gastric residence structure of claim 15,wherein the central elastic polymeric component comprises a polymerselected from the group consisting of polyesters, polyethers,polysiloxanes, polyamides, polyacrylates, polymethacrylates,polyanhydrides, and polyurethanes.
 24. The gastric residence structureof claim 15, wherein the plurality of loadable polymeric componentscomprise polycaprolactone (PCL), poly(ethylene-co-vinyl acetate), orpolyethylene glycol (PEG).
 25. The gastric residence structure of claim15, wherein the folded shape has a convex hull at least about 10% lessthan a convex hull of the open retention shape.
 26. The gastricresidence structure of claim 15, wherein the folded shape has a largestcross-sectional dimension at least about 10% less than a largestcross-sectional dimension of the open retention shape.
 27. A method fordelivering a residence structure, comprising: administering, to asubject, a containing structure containing a gastric residence structureas in claim
 20. 28. The method of 27, wherein the subject is a human.29. A gastric residence structure comprising: at least three loadablepolymeric components; and a central elastic polymeric component; whereinthe at least three loadable polymeric components are connected to thecentral elastic polymeric component via separate linker components,wherein the gastric residence structure is configured to be folded andphysically constrained during administration and is configured to assumean open retention shape upon removal of a constraint, wherein changebetween the folded shape and the open retention shape is mediated by theelastic polymeric component that undergoes elastic deformation when theresidence structure is in the folded shape and recoils when the gastricresidence structure assumes the open retention shape, and wherein one ormore of said separate linker components degrades, dissolves,disassociates, or mechanically weakens in a gastric environment whichresults in loss of retention shape and passage out of a gastric cavity.30. The gastric residence structure of claim 29, wherein the at leastthree loadable polymeric components comprise at least about 60 wt % ofthe total structure weight.
 31. The gastric residence structure of claim29, wherein the gastric residence structure has a folding force of atleast about 0.2 N.
 32. The gastric residence structure of claim 29,wherein the residence structure has an open cross-sectional dimension ofat least about 2 cm.
 33. The gastric residence structure of claim 29,wherein the residence structure is configured such that it is retainedin the gastric cavity for at least about 24 hours.
 34. The gastricresidence structure of claim 29, wherein one or more of the at leastthree loadable polymeric components comprise an active substance. 35.The gastric residence structure of claim 34, wherein the gastricresidence structure is configured such that the active substance isreleased from the at least three loadable polymeric components at aparticular initial average rate as determined over the first 24 hours ofrelease, and wherein the active substance is released at an average rateof at least about 1% of the initial average rate over a 24 hour periodafter the first 24 hours of release.
 36. The gastric residence structureof claim 29, wherein the open retention shape is a multi-armed starshape.
 37. The gastric residence structure of claim 29, wherein thecentral elastic polymeric component comprises a polymer selected fromthe group consisting of polyesters, polyethers, polysiloxanes,polyamides, polyacrylates, polymethacrylates, polyanhydrides, andpolyurethanes.
 38. The gastric residence structure of claim 29, whereinthe at least three loadable polymeric components comprisepolycaprolactone (PCL), poly(ethylene-co-vinyl acetate), or polyethyleneglycol (PEG).
 39. The gastric residence structure of claim 29, whereinthe folded shape has a convex hull at least about 10% less than a convexhull of the open retention shape.
 40. The gastric residence structure ofclaim 29, wherein the folded shape has a largest cross-sectionaldimension at least about 10% less than a largest cross-sectionaldimension of the open retention shape.
 41. A method for delivering aresidence structure, comprising: administering, to a subject, acontaining structure containing a gastric residence structure as inclaim
 34. 42. The method of 41, wherein the subject is a human.